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UBC Theses and Dissertations

Metoclopramide disposition in normal and uremic humans Wright, Matthew Rowland 1987

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METOCLOPRAMIDE DISPOSITION IN NORMAL AND UREMIC HUMANS by MATTHEW ROWLAND WRIGHT B.Sc.(Pharm.); U n i v e r s i t y o f B r i t i s h Columbia, 1985 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS OF THE DEGREE OF MASTER OF SCIENCE i n THE FACULTY OF GRADUATE STUDIES ( F a c u l t y o f Pharmaceutical Sciences) D i v i s i o n o f Pharmaceutics We accept t h i s t h e s i s as conforming t o the r e q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA June 1987 (c) Matthew Rowland Wright, 1987 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department The University of British Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 DE-6(3/81) ABSTRACT Metoclopramide (MCP) i s a p o t e n t a n t i n a u s e a n t / a n t i e m e t i c and g a s t r o i n t e s t i n a l m o t i l i t y m o d i f i e r . MCP f i n d s c l i n i c a l use i n a wide v a r i e t y of s i t u a t i o n s and i s a d m i n i s t e r e d on both an acute and c h r o n i c b a s i s . T h i s t h e s i s examines the ph a r m a c o k i n e t i c s o f MCP i n both normal, h e a l t h y v o l u n t e e r s and i n uremic s u b j e c t s on a maintenance h e m o d i a l y s i s program. S p e c i f i c a l l y , i n the normal, h e a l t h y v o l u n t e e r s , the d o s e - l i n e a r i t y , and a b s o l u t e and r e l a t i v e b i o a v a i l a b i l i t i e s are examined. In the uremics, the e f f e c t s of c h r o n i c r e n a l f a i l u r e on MCP k i n e t i c s , the removal of MCP by h e m o d i a l y s i s , and t h e e f f e c t s of h e m o d i a l y s i s on MCP k i n e t i c s are examined. Based on e a r l y r e p o r t s , the p h a r m a c o k i n e t i c s o f MCP were c l a i m e d t o be dose-dependent and the a b s o l u t e b i o a v a i l a b i l i t y extremely v a r i a b l e . However, many o f t h e s e e a r l y s t u d i e s s u f f e r e d from m e t h o d o l o g i c a l problems which l i m i t the c r e d i b i l i t y of t h e i r f i n d i n g s . Based on a four-way c r o s s o v e r study i n v o l v i n g s i x normal, h e a l t h y v o l u n t e e r s we f i n d , i n c o n t r a s t t o p r e v i o u s r e s u l t s , t h a t t h e k i n e t i c s of MCP are l i n e a r over the dose range of 5 -20 mg, the a b s o l u t e b i o a v a i l a b i l i t y i s 76 + 38 %, and the r e l a t i v e b i o a v a i l a b i l i t y o f a s o l u t i o n dosage form vs the t a b l e t dosage form i s approximately 1. i i i Although r e n a l c l e a r a n c e accounts f o r o n l y about 20 % o f t h e t o t a l body c l e a r a n c e o f MCP i n normals, uremia has been shown t o s u b s t a n t i a l l y a l t e r MCP k i n e t i c s i n both r a t and man. There appears t o be a t l e a s t a t w o - f o l d decrease i n t o t a l body c l e a r a n c e w i t h an at t e n d e n t , p r o p o r t i o n a l i n c r e a s e i n e l i m i n a t i o n h a l f - l i f e and i n s i g n i f i c a n t change i n volume o f d i s t r i b u t i o n . H e m o d i a l y s i s i s r e l a t i v e l y i n e f f e c t i v e i n c l e a r i n g MCP from the body and t h i s i n e f f i c i e n c y i s p r o b a b l y r e l a t e d t o t h e r e l a t i v e l y l a r g e volume of d i s t r i b u t i o n o f MCP. He m o d i a l y s i s a l s o has no e f f e c t s on the apparent k i n e t i c parameters f o l l o w i n g i t s t e r m i n a t i o n . In a d d i t i o n , r e s u l t s from a s i n g l e p a t i e n t who r e c e i v e d a kidney t r a n s p l a n t show t h a t the renewed r e n a l f u n c t i o n i s accompanied by an apparent r e v e r s i o n o f a l l k i n e t i c parameters t o w i t h i n normal l i m i t s w i t h i n 15 days o f t r a n s p l a n t a t i o n . i v TABLE OF CONTENTS CHAPTER PAGE ABSTRACT i i LIST OF TABLES v i i LIST OF FIGURES v i i i LIST OF SCHEMES x ABBREVIATIONS x i ACKNOWLEDGEMENTS x i v 1 INTRODUCTION 1 1.1 Metoclopramide Pharmacology and C l i n i c a l 1 A p p l i c a t i o n s 1.2 E f f e c t o f Route of A d m i n i s t r a t i o n on 8 Pharmacokinetics 1.3 D o s e - l i n e a r i t y o f K i n e t i c s 12 1.4 E f f e c t s of Chro n i c Renal F a i l u r e on 14 Pharmacokinetics 1.4.1 A b s o r p t i o n and B i o a v a i l a b i l i t y 15 1.4.2 D i s t r i b u t i o n and P r o t e i n B i n d i n g 17 1.4.3 Metabolism 20 1.4.4 E l i m i n a t i o n o f I n t a c t Drug and 22 M e t a b o l i t e s 1.5 I n f l u e n c e o f Hemodialysis on Drug 25 Removal 1.6 Metoclopramide Pharmacokinetics 28 1.6.1 Animal Models 28 1.6.2 Humans 30 2 EXPERIMENTAL 34 2.1 M a t e r i a l s and S u p p l i e s 34 V 2.1.1 Chemicals 34 2.1.2 Reagents 34 2.1.3 S o l v e n t s 35 2.1.4 Gases 35 2.1.5 S u p p l i e s f o r human experiments 35 2.2 Equipment 36 2.3 P r e p a r a t i o n o f S o l u t i o n s 37 2.3.1 Metoclopramide.HCl.H 0 37 2.3.2 M a p r o t a l i n e . H C l ( i n t e r n a l standard) 37 2.3.3 Reagent s o l u t i o n s 38 2.4 Sample E x t r a c t i o n Procedure 38 2.4.1 Plasma e x t r a c t i o n 38 2.4.2 D e r i v a t i z a t i o n 39 2.5 Standard Curve P r e p a r a t i o n f o r Fused S i l i c a 41 C a p i l l a r y GC-ECD A n a l y s i s 2.6 C a p i l l a r y GC-ECD 41 2.6.1 GC-ECD Parameters 41 2.6.2 A p p l i c a t i o n o f assay t o uremic plasma 42 2.7 Pharmacokinetic S t u d i e s i n Normal and Uremic 42 Humans 2.7.1 Experimental p r o t o c o l i n normal, h e a l t h y 42 v o l u n t e e r s . 2.7.2 Q u a n t i t a t i v e plasma a n a l y s i s i n normals 46 2.7.3 Experimental p r o t o c o l i n uremic 4 6 v o l u n t e e r s 2.7.4 Q u a n t i t a t i v e plasma a n a l y s i s i n uremics 49 2.7.5 Experimental p r o t o c o l i n kidney 49 t r a n s p l a n t r e c i p i e n t 2.7.6 Q u a n t i t a t i v e plasma a n a l y s i s i n kidney 50 t r a n s p l a n t r e c i p i e n t 2.8 Data A n a l y s i s 50 2.8.1 Computer f i t t i n g 50 2.8.2 Pharmacokinetic c a l c u l a t i o n s 51 2.8.3 S t a t i s t i c a l t e s t s 52 3 RESULTS 53 3.1 A p p l i c a b l i t y o f assay t o uremic serum. 53 vi 3.1.1 E x t r a c t i o n o f blank plasma 53 3.1.2 Standard curve 53 3.2 Normal pharm a c o k i n e t i c s 56 3.2.1 Plasma K i n e t i c s 56 3.2.2 U r i n a r y E x c r e t i o n 60 3.3 Uremic pharm a c o k i n e t i c s 62 3.3.1 24 hour p r e d i a l y s i s dose 62 3.3.2 1 hour p r e d i a l y s i s dose 68 3.4 Pharmacokinetics i n kidney t r a n s p l a n t 68 r e c i p i e n t 3.4.1 Plasma K i n e t i c s 68 3.4.2 U r i n a r y E x c r e t i o n 74 4 DISCUSSION 77 4.1 A p p l i c a b i l i t y o f Assay t o Uremic Plasma 77 4.2 Normal Pharmacokinetics 78 4.3 Uremic Pharmacokinetics 89 5 SUMMARY AND CONCLUSIONS 99 6 REFERENCES 100 7 APPENDIX 116 v i i LIST OF TABLES TABLE PAGE 1 F a c t o r s a f f e c t i n g drug b i o a v a i l a b i l i t y 10 2 Metoclopramide k i n e t i c parameters o b t a i n e d 57 from plasma o f h e a l t h y v o l u n t e e r s 3 Metoclopramide pharmacokinetic parameters , 63 o b t a i n e d from u r i n e data o f h e a l t h y v o l u n t e e r s 4 Metoclopramide k i n e t i c parameters from the 64 cumulated u r i n e and plasma r e s u l t s o f the normal, h e a l t h y v o l u n t e e r s 5 C l i n i c a l d e t a i l s o f uremic p a t i e n t s 65 6 D e t a i l s p e r t a i n i n g t o the d i a l y s i s o f 66 the uremic p a t i e n t s . 7 Metoclopramide pharmacokinetic parameters 67 from uremic v o l u n t e e r s 24 h p r i o r t o d i a l y s i s . 8 Metoclopramide pharmacokinetic parameters 70 from uremic v o l u n t e e r s l h p r i o r t o d i a l y s i s . 9 C l i n i c a l parameters f o r uremic p a t i e n t BM 72 b e f o r e and a f t e r kidney t r a n s p l a n t a t i o n . 10 Metoclopramide pharmacokinetic parameters 75 f o r uremic v o l u n t e e r BM b e f o r e and a f t e r kidney t r a n s p l a n t a t i o n . 11 Metoclopramide Pharmacokinetic parameters 76 from the u r i n e o f the kidney t r a n s p l a n t r e c i p i e n t v i i i LIST OF FIGURES FIGURE PAGE 1 S t u c t u r e o f Metoclopramide 1 2 D e t t l i Nomogram 24 3 R e p r e s e n t a t i v e Chromatograms o f E x t r a c t e d Uremic Blank Plasma 54 4 Standard Curve 55 5 Mean Area Under the Plasma C o n c e n t r a t i o n vs Time Curve 58 6 R e p r e s e n t a t i v e Plasma C o n c e n t r a t i o n v s Time P r o f i l e s f o r a S i n g l e H e a l t h y V o l u n t e e r . 5 mg O r a l S o l u t i o n (0—0) , 10 mg O r a l S o l u t i o n (o—n) , 10 mg IV Bolus (•—•) , 20 mg O r a l S o l u t i o n (•—«) 59 7 R e p r e s e n t a t i v e Amount Remaining t o be E x c r e t e d i n the U r i n e f o r a S i n g l e , H e a l t h y V o l u n t e e r . 5 mg O r a l S o l u t i o n ( o — o) , 10 mg O r a l S o l u t i o n (•—o) , 10 mg IV Bolus (•—•) , 2 0 mg O r a l S o l u t i o n (•— •) 61 8 R e p r e s e n t a t i v e Plasma C o n c e n t r a t i o n v s Time P r o f i l e f o r a 10 mg IV Bolus Dose Given to a Uremic V o l u n t e e r 24 h P r i o r to H e m o d i a l y s i s . 69 P r i o r t o D i a l y s i s , D i a l y s i s ; a r t e r i a l c o n c e n t r a t i o n — •) , venous c o n c e n t r a t i o n ( D - D ) . R e p r e s e n t a t i v e Plasma C o n c e n t r a t i o n v s Time P r o f i l e f o r a 10 mg IV Bolus Dose Giv e n t o a Uremic V o l u n t e e r 1 h P r i o r t o H e m o d i a l y s i s . P r i o r t o D i a l y s i s (•-•), D i a l y s i s ; a r t e r i a l c o n c e n t r a t i o n (•—•) , venous c o n c e n t r a t i o n ( D — D ) , P o s t - d i a l y s i s (o—o) • Plasma C o n c e n t r a t i o n vs Time P r o f i l e s f o r t h e Kidney T r a n s p l a n t R e c i p i e n t F o l l o w i n g 10 mg IV Bolus Dose. Uremia (• —•) , 15 days A f t e r T r a n s p l a n t (o—o) , 3 months A f t e r T r a n s p l a n t X LIST OF SCHEMES SCHEME PAGE 1 E x t r a c t i o n Procedure 40 2 Study P r o t o c o l i n Normal Hea l t h y V o l u n t e e r s 45 3 Study P r o t o c o l i n Uremic V o l u n t e e r s 48 x i ABBREVIATIONS AAG A l p h a - l - A c i d G l y c o p r o t e i n A.D.M.E. A b s o r p t i o n , D i s t r i b u t i o n , Metabolism, E l i m i n a t i o n A l k Phos A l k a l i n e Phosphatase ARE Amount Remaining t o be Ex c r e t e d ANOVA A n a l y s i s o f V a r i a n c e AUC Area Under the Plasma C o n c e n t r a t i o n v s Time Curve A-V A r t e r i o - v e n o u s BUN Blood Urea N i t r o g e n C l d D i a l y s e r C l e a r a n c e C l i n t I n t r i n s i c C l e a r a n c e CRTZ Chemoreceptor T r i g g e r Zone C V . C o e f f i c i e n t o f V a r i a t i o n E E x t r a c t i o n E f f i c i e n c y ECD E l e c t r o n Capture D e t e c t i o n F B i o a v a i l a b i l i t y FID Flame I o n i z a t i o n D e t e c t i o n g A c c e l e r a t i o n due t o g r a v i t y GC-ECD Gas Chromatographic E l e c t r o n Capture D e t e c t i o n GI G a s t r o i n t e s t i n a l HFB H e p t a f l u o r o b u t y r y l HFB-MAP HFB-MCP I.D. IV Ka K n o r K E LES MAP.HCl MCP MCP.HCl MCP.HC1.H20 r 2 RBC S c r or s.d. or s t d dev SGOT SGPT H e p t a f l u o u r o b u t y r y l d e r i v a t i v e of m a p r o t a l i n e H e p t a f l u o r o b u t y r y l d e r i v a t i v e t o f metoclopramide I n t e r n a l Diameter Intravenous A b s o r p t i o n r a t e Constant Terminal E l i m i n a t i o n Rate Constant Lower Esophageal S p h i n c t e r M a p r o t a l i n e H y d r o c h l o r i d e Metoclopramide Metoclopramide H y d r o c h l o r i d e Metoclopramide H y d r o c h l o r -i d e Monohydrate C o e f f i c i e n t o f De t e r m i n a t i o n Red Blood C e l l Serum C r e a t i n i n e Standard d e v i a t i o n Serum Glutamate O x a l a t e Transaminase Serum Glutamate Pyruvate Transaminase E l i m i n a t i o n h a l f - l i f e Volume of D i s t r i b u t i o n Volume of the C e n t r a l Compartment ACKNOWLEDGEMENTS The author i s deeply indebted t o Dr. James A x e l s o n f o r h i s encouragement, f r i e n d s h i p , and support d u r i n g the cour s e o f t h i s work. S i n c e r e thanks a l s o t o Dr. John P r i c e f o r h i s enthusiasm, c o n s t r u c t i v e c r i t i c i s m , and guidance d u r i n g t h i s p r o j e c t . Thanks a l s o t o Dr. Frank Abbott, Dr. John S i n c l a i r , and Dr. James O r r f o r t h e i r guidance. The a s s i s t a n c e , guidance, and f r i e n d s h i p o f Mr. Wayne Riggs i s g r e a t l y a p p r e c i a t e d and warmly r e c o g n i z e d . A l s o the support and encouragement o f Mr. Sun Dong Yoo and Ms. Grace Lap-Yu Chan are v e r y much a p p r e c i a t e d . The a s s i s t a n c e d u r i n g the human ex p e r i m e n t a t i o n , p a t i e n c e , and f r i e n d s h i p o f Mrs. Barbara McErlane are g r e a t l y a p p r e c i a t e d . A l s o the d e d i c a t i o n and a s s i s t a n c e o f Ms. Nora Wong, d u r i n g the uremic v o l u n t e e r s t u d i e s a re warmly r e c o g n i z e d . The author i s a l s o g r a t e f u l t o MRC f o r the s t u d e n t s h i p awarded him. the memory of my grandfather , Rev. K. S t . C. Thomas. 1 1. INTRODUCTION 1.1 Metoclopramide Pharmacology and C l i n i c a l A p p l i c a t i o n s I n t r o d u c t i o n o f a methoxy group onto t h e h e t e r o c y c l i c r i n g o f procainamide produces compounds w i t h a n t i e m e t i c a c t i v i t y ( C l i n t o n and Laskowsky, 1955). The a n t i e m e t i c a c t i v i t y o f these congeners can be enhanced by the a d d i t i o n of a halogen atom para t o the methoxy group (Besancon e t a l . , 1964). Metoclopramide i s the 2-methoxy, 5 - c h l o r o analogue of procainamide (see F i g u r e 1) • F i g u r e 1: Metoclopramide The pharmacology and c l i n i c a l a p p l i c a t i o n s o f metoclopramide (MCP) have been e x t e n s i v e l y reviewed by s e v e r a l a u t hors (Pinder e t a l . , 1976; H a r r i n g t o n e t a l . , 1983; A l b i b i and McCallum, 1983; Shaughnessy, 1985; Desmond and Watson, 1986). Although i t i s an analog of procainamide, MCP does not possess s i g n i f i c a n t 2 a n t i a r r h y t m i c o r l o c a l a n a e s t h e t i c p r o p e r t i e s ( H a r r i n g t o n e t a l . . 1983). The p h a r m a c o l o g i c a l a c t i o n s o f MCP are most pronounced i n the g a s t r o i n t e s t i n a l t r a c t where a g e n e r a l i z e d i n c r e a s e i n m o t i l i t y i s seen a f t e r e i t h e r o r a l o r i n t r a v e n o u s a d m i n i s t r a t i o n (Pinder e t a l . . 1976; S c h u l z e - D e l r i e u , 1981). Segmentally, w i t h i n the G l t r a c t , MCP has s e v e r a l e f f e c t s . In the esophagus, MCP r a i s e s the p r e s s u r e o f the lower esophageal s p h i n c t e r (LES), i n a dose-dependent f a s h i o n , i n both normal v o l u n t e e r s and p a t i e n t s w i t h h i a t u s h e r n i a and t o a l e s s e r e x t e n t i n pregnant women (Baumann e t a l . . 1979; Behar and B i a n c a n i a , 1976; Brock-Utne e t a l . . 1978). In a d d i t i o n , MCP a l s o enhances the amplitude and d u r a t i o n of esophageal p e r i s t a l s i s as w e l l as improving a c i d c l e a r a n c e from the esophagus (Desmond and Watson, 1986). MCP s i g n i f i c a n t l y a c c e l e r a t e s g a s t r i c emptying and the amplitude o f g a s t r i c c o n t r a c t i o n ( H a r r i n g t o n e t a l . . 1983). The e f f e c t s o f MCP on the stomach are most r e a d i l y seen i n p a t i e n t s w i t h slow g a s t r i c emptying r a t e s or s m a l l and/or slow a n t r a l and duodenal c o n t r a c t i o n s ( H a r r i n g t o n e t a l . . 1983). The most pronounced e f f e c t s w i t h i n the stomach are on the a n t r a l r e g i o n where MCP induces c o n t r a c t i o n as w e l l as improving c o o r d i n a t i o n o f a n t r a l and duodenal c o n t r a c t i o n (Pinder e t a l . . 1976). MCP has no e f f e c t s on the amount of g a s t r i c a c i d s e c r e t e d or on serum g a s t r i n l e v e l s (Cohen e t a l . . 1976). In the s m a l l i n t e s t i n e , MCP decrea s e s i n t e s t i n a l t r a n s i t time v i a a s t i m u l a t i o n o f smooth muscle c o n t r a c t i o n which can be antagonized by a n t i c h o l i n e r g i c agents (Pinder e t a l . f 1976). As w e l l , improvement o f a n t r a l / d u o d e n a l c o n t r a c t i o n c o o r d i n a t i o n and an i n c r e a s e i n the amplitude o f duodenal c o n t r a c t i o n has been noted ( H a r r i n g t o n e t a l . . 1983). MCP appears t o be a s t r o n g e r s t i m u l a n t o f i n t e s t i n a l m o t i l i t y than i s p y r i d o s t i g m i n e bromide (Oigaard and F l e c k e n s t e i n , 1975). Although a s t i m u l a n t o f both amplitude and frequency o f c o n t r a c t i o n i n i n v i t r o s t r i p s o f c o l o n i c c i r c u l a r smooth muscle ( S c h u l z e - D e l r i e u , 1979), no c o n s i s t e n t e f f e c t s o f MCP on the l a r g e i n t e s t i n e have been demonstrated i n v i v o ( H a r r i n g t o n e t a l . , 1983). No c o n s i s t a n t e f f e c t s o f MCP on the g a l l b l a d d e r i n v i v o i n animals or humans have been noted (Pinder e t a l . . 1976). The exact mechanism of MCP a c t i o n i n the GI t r a c t i s u n c l e a r . However, many a c t i o n s are i n h i b i t e d by a n t i c h o l i n e r g i c agents ( H a r r i n g t o n e t a l . , 1983). MCP has no a n t i c h o l i n e s t e r a s e a c t i v i t y and i t s a c t i o n s are not i n f l u e n c e d by g a n g l i o n i c b l o c k i n g agents (Pinder e t  a l . . 1976). S i n c e vagotomy does not a f f e c t MCP a c t i v i t y , t h e s i t e o f a c t i o n i n the GI t r a c t i s thought t o be a t the p e r i p h e r a l nerve endings i n the gut smooth muscle (Stadaas and Aune, 1971). There are t h r e e proposed 4 mechanisms used t o e x p l a i n the a c t i v i t y of MCP i n the GI t r a c t : 1. P o t e n t i a t i o n of c h o l i n e r g i c a c t i v i t y A lthough MCP i s not c h o l i n o m i m e t i c i n t h e manner of t r a d i t i o n a l c h o l i n e r g i c a g o n i s t s , many a c t i o n s of MCP are a n tagonized by a n t i c h o l i n e r g i c agents ( E i s n e r , 1968). Vagotomy, however, does not a b o l i s h MCP a c t i v i t y (Stadaas and Aune, 1971), s u g g e s t i n g t h a t a c t i v i t y depends on i n t r a m u r a l c h o l i n e r g i c neurons (Desmond and Watson, 1986). U s i n g the i s o l a t e d guinea p i g stomach Hay and Man (1979) have demonstrated t h a t MCP a c t i v i t y i s dependent on the r e l e a s e o f a c e t y l c h o l i n e from neuronal s t o r e s w i t h i n the e n t e r i c nervous system. F u r t h e r evidence from i s o l a t e d human and guinea p i g GI smooth muscle suggests t h a t MCP augments a c e t y l c h o l i n e r e l e a s e and s e n s i t i z e s m u s c a r i n i c r e c e p t o r s (Beani e t a l . , 1970). 2. Dopamine Antagonism Dopamine i s w e l l known t o be a n e u r o t r a n s m i t t e r i n the c e n t r a l , p e r i p h e r a l , and e n t e r i c nervous systems. MCP has been shown t o be a b l e t o antagonize L-dopa mediated d e l a y s o f g a s t r i c emptying and L-dopa ant a g o n i z e s MCP induced i n c r e a s e s i n LES tone (Berkowitz and McCallum, 1980; Baumann e t a l . , 1979). 5 3. D i r e c t A c t i o n on Smooth Muscle In an i n v i t r o p r e p a r a t i o n o f oppossum esophageal muscle, a p p l i c a t i o n o f MCP r e s u l t e d i n d o s e - r e l a t e d i n c r e a s e s i n t e n s i o n (Cohen and DiMarino, 1976). Although tenuous, t h i s o b s e r v a t i o n suggests t h a t some d i r e c t a c t i o n o f MCP may be p o s s i b l e . In a d d i t i o n t o i t s e f f e c t s on the GI t r a c t , MCP possesses c e n t r a l e f f e c t s t h a t a re l i k e l y as important t o i t s o v e r a l l a n t i e m e t i c e f f i c a c y as the i n c r e a s e d GI t r a c t m o t i l i t y (Desmond and Watson, 1986). MCP i s b e l i e v e d t o r a i s e the t h r e s h o l d o f the chemoreceptor t r i g g e r zone (CRTZ) and decrease the s e n s i t i v i t y o f v i s c e r a l a f f e r e n t s which p r o j e c t t o the emetic c e n t r e i n the l a t e r a l r e t i c u l a r f o r m a t i o n (Pinder e t a l . . 1976). S i n c e s t i m u l a t i o n o f the CRTZ i s r e l a t i v e l y s p e c i f i c t o dopamine a g o n i s t i c drugs, c e n t r a l l y a c t i n g agents which b l o c k t h i s a re g e n e r a l l y c o n s i d e r e d t o be dopamine a n t a g o n i s t s (Cannon, 1975). MCP a l s o demonstrates b e h a v i o u r a l e f f e c t s i n animals and adverse e f f e c t s i n man c o n s i s t e n t w i t h the p r o p o s i t i o n t h a t i t i s a dopamine a n t a g o n i s t ( H a r r i n g t o n e t a l . . 1983) . Jenner e t a l . (1978) have determined t h a t the benzamides i n t e r a c t w i t h a non-adenylate c y c l a s e coupled dopamine r e c e p t o r , thus MCP may be c l a s s i f i e d as a s e l e c t i v e D-2 r e c e p t o r a n t a g o n i s t . 6 S i n c e MCP i s a dopamine a n t a g o n i s t i t i s a l s o a b l e t o a f f e c t the r e l e a s e of v a r i o u s hormones. MCP s t i m u l a t e s p r o l a c t i n r e l e a s e as w e l l as s l i g h t l y i n c r e a s i n g serum t h y r o t r o p i n , a l d o s t e r o n e , and a r g i n i n e v a s o p r e s s i n l e v e l s (Desmond and Watson, 1986). In c o n t r a s t , MCP causes s l i g h t r e d u c t i o n s i n growth hormone, l u t e i n i z i n g hormone, and f o l l i c l e - s t i m u l a t i n g hormone l e v e l s (Desmond and Watson, 1986). Although MCP i s s t r u c t u r a l l y r e l a t e d t o procainamide, i t does not have s i g n i f i c a n t e f f e c t s on b l o o d p r e s s u r e or i n t r a c a r d i a c e l e c t r i c a l c o n d u c t i o n i n animal s t u d i e s ( H a r r i n g t o n e t a l . . 1983). However, i s o l a t e d i n s t a n c e s of hypotension under g e n e r a l a n a e s t h e s i a , h y p e r t e n s i v e c r i s i s i n p a t i e n t s w i t h pheochromocytoma, and c a r d i a c arrhythmias have been r e p o r t e d i n man. MCP, however, has been r e p o r t e d t o decrease r e n a l plasma flow i n oncology p a t i e n t s ( I s r a e l e t a l . , 1986) by l e s s than 20%. A l t e r n a t i v e l y , Tarn e t  a l . (1981) demonstrated a decrease i n h e p a t i c b l o o d flow, brought about by MCP, i n the r a t . MCP has found c l i n i c a l use i n a wide v a r i e t y o f s e t t i n g s both i n Europe and North America. S e v e r a l reviews have e x t e n s i v e l y examined these uses (Pinder e t  a l . . 1976, H a r r i n g t o n e t a l . . 1983; A l b i b i and McCallum, 1983; Shaughnessy, 1985; Desmond and Watson, 1986). MCP has found use i n c o n t r o l l i n g nausea and v o m i t i n g r e s u l t i n g from a v a r i e t y of e t i o l o g i e s . More s p e c i f i c a l l y MCP i s e f f e c t i v e i n c o n t r o l l i n g the nausea and v o m i t i n g a s s o c i a t e d w i t h uremia (Jones, 1968), i n p o s t o p e r a t i v e p a t i e n t s (Pinder e t a l . , 1976), n a r c o t i c t h e r a p y (Assaf e t a l . . 1974), cancer chemotherapy ( i n p a r t i c u l a r c i s - p l a t i n ) ( H a r r i n g t o n e t a l . . 1983), r a d i a t i o n s i c k n e s s (Ward, 1973), and pregnancy (Singh and Lean, 1973). A d d i t i o n a l l y MCP has found use i n g a s t r o e s o p h a g e a l r e f l u x treatment ( H a r r i n g t o n e t a l . , 1983), g a s t r o p a r e s i s a s s o c i a t e d w i t h vagotomy and g a s t r i c r e s e c t i o n or d i a b e t e s (Desmond and Watson, 1986), mi g r a i n e t h e r a p y t o enhance the d e l i v e r y of a n t i m i g r a i n o u s agents (Matts, 1974), GI t r a c t d i a g n o s t i c and r a d i o l o g i c a l procedures ( C h r i s t i e and Ament, 1976; James and Hume, 1968), and s i g n i f i c a n t l y p r i o r t o a n a e s t h e t i c i n d u c t i o n as i n emergency c a e s a r i a n s e c t i o n (Schulze-^Delrieu, 1981) . Furthermore, o t h e r t r i a l s have examined the e f f e c t i v e n e s s o f MCP i n d e f e c t i v e l a c t a t i o n , treatment of p a t i e n t s w i t h hypomotile u r e t e r , o r t h o s t a t i c h y p o t e n s i o n , h i c c u p s , t a r d i v e d y s k i n e s i a , and v e r t i g o ( H a r r i n g t o n e t a l . . 1983). Adverse e f f e c t s of MCP are g e n e r a l l y t r a n s i e n t and r e v e r s i b l e and occur i n approximately 11% o f p a t i e n t s i n some o f the l a r g e r c l i n i c a l surveys ( H a r r i n g t o n e t a l . , 1983). S e v e r a l p a t i e n t groups, e.g. uremics and 8 c h i l d r e n , appear t o be a t somewhat h i g h e r r i s k f o r t h e development o f adverse e f f e c t s t o MCP. Drowsiness and r e s t l e s s n e s s appear t o be the most common s i d e e f f e c t s o c c u r r i n g i n about 10% o f p a t i e n t s w h i l e e x t r a p y r a m i d a l s i d e e f f e c t s occur i n about 9% o f p a t i e n t s ( H a r r i n g t o n e t a l . . 1983). Other s i d e e f f e c t s appear t o occur i n l e s s than 5 % o f p a t i e n t s ( H a r r i n g t o n e t a l . . 1983). 1.2 E f f e c t of Route o f A d m i n i s t r a t i o n on Drug K i n e t i c s Based on s t u d i e s u s i n g p-aminohippuric a c i d and s e v e r a l sulfonamide a n t i b a c t e r i a l s , which were a d m i n i s t e r e d t o experimental animals both IV and o r a l l y , Dost (1958) and Gladtke (1964) proposed a r e l a t i o n s h i p between dose and area under t h e plasma c o n c e n t r a t i o n vs time curve (AUC) known as "the law of c o r r e s p o n d i n g a r e a s " . T h i s "law" suggested t h a t , i f d i s t r i b u t i o n , metabolism and e x c r e t i o n a r e f i r s t - o r d e r p r o c e s s e s , then the AUC i s d i r e c t l y p r o p o r t i o n a l t o the dose and i s independent of the r o u t e of a d m i n i s t r a t i o n . U n f o r t u n a t e l y , the drugs used t o formulate t h i s p r o p o s i t i o n are o n l y n e g l i g i b l y o r s l o w l y m e t a b o l i z e d by the l i v e r and are not r e p r e s e n t a t i v e of enough drugs t o e s t a b l i s h such a g e n e r a l i t y ( H a r r i s and Riegelman, 1969). In f a c t , i t has become q u i t e c l e a r t h a t f o r many drugs the AUC i s dependent not o n l y upon the dose but a l s o on 9 t h e r o u t e o f a d m i n i s t r a t i o n , p h y s i o l o g i c a l f a c t o r s o f the e x p e r i m e n t a l animal, and the p h y s i c o - c h e m i c a l p r o p e r t i e s o f the drug and dosage form. T h i s concept i s b e s t expressed by the term b i o a v a i l a b i l i t y , which, i n i t s s i m p l e s t terms r e f e r s t o the r a t e and e x t e n t o f drug a b s o r p t i o n ( G i b a l d i and P e r r i e r , 1982). As p r e v i o u s l y mentioned, and as i s somewhat i n t u i t i v e , the amount of drug r e a c h i n g the systemic c i r c u l a t i o n i s a f f e c t e d by both p h y s i o l o g i c a l f a c t o r s of the t e s t animal and the p h y s i c o - c h e m i c a l f a c t o r s of the drug and dosage form, as o u t l i n e d i n the f o l l o w i n g t a b l e (Riegelman and Rowland, 1973) . The most r e l i a b l e d e t e r m i n a t i o n of b i o a v a i l a b i l i t y i s made by the comparison o f the AUC's o f equal doses of drug t o e x p e r i m e n t a l s u b j e c t s on a c r o s s o v e r b a s i s by o r a l and IV r o u t e s . For a drug d i s p l a y i n g n compartmental k i n e t i c s : F Dose o r a l AUC o r a l V. B K n Dose IV and AUC TV V. B K. n t h e r e f o r e : TABLE 1 Factors affecting drug b i o a v a i l a b i l i t y (Riegelman and Rowland, 1973) Physiological FactorB Dosage Form Factors Properties of lumenal f l u i d s hydrogen ion concentration mucous interaction complexing components surface a c t i v i t y b i l e interaction Factors affecting Gl tran s i t gastric emptying rate food effects motility enterohepatic cycling Factors at absorption s i t e surface area permeability of barrier specialized transport local blood flow intestinal metabolism Metabolic aspects hepatic metabolism enzyme levels hepatic portal blood flow drug binding proteins extrahepatic metabolism saturation phenomena gut wall metabolism Distribution effects plasma protein levels obesity Disease states achlorhydria thyrotoxicosis b i l i a r y atresia congestive heart f a i l u r e Physical properties of drug water s o l u b i l i t y l i p i d s o l u b i l i t y p a r t i t i o n coefficient pK Properties of the dosage form disintegration time dissolution rate surface area crystal size solvates s a l t form excipients Manufacturing variables granulation process lubricant concentration compression pressure tablet coating Pharmacological effects of drugs modification of blood flow parasympatholytic a c t i v i t y 11 t h u s : AUC o r a l Dose IV F = AUC IV Dose o r a l T h i s e q u a t i o n suggests t h a t unequal doses may be used t o determine b i o a v a i l a b i l i t y , however, t h i s presupposes t h a t d o s e - l i n e a r k i n e t i c s e x i s t . T h e r e f o r e , i n t he absence o f i n f o r m a t i o n r e g a r d i n g d o s e - l i n e a r i t y , equal doses s h o u l d be used. Independently o f the AUC determined from plasma sampling, b i o a v a i l a b i l t y may be a l s o be determined from the t o t a l amount o f drug e x c r e t e d i n t a c t i n the u r i n e . T h i s method r e q u i r e s complete u r i n e c o l l e c t i o n f o r a p e r i o d o f a t l e a s t 7 h a l f - l i v e s w i t h a t l e a s t 10% o f the dose b e i n g e x c r e t e d unchanged. G e n e r a l l y , t h i s assessment sh o u l d be c a r r i e d out i n c o n j u n c t i o n w i t h d e t e r m i n a t i o n o f the b i o a v a i l a b i l i t y from plasma data s i n c e i t g i v e s independent c o n f i r m a t i o n o f the r e s u l t s o b t a i n e d from plasma. As s t a t e d p r e v i o u s l y , the l i t e r a t u r e c o n t a i n s many examples of drugs t h a t are not completely b i o a v a i l a b l e ( i . e . A U C o r a ^ < AUCjy). In many cases, t h e d i s p o s i t i o n of t h e s e drugs i s markedly i n f l u e n c e d by the r o u t e o f a d m i n i s t r a t o n . I f a drug i s g i v e n by a p e r i p h e r a l r o u t e (e.g. s u b l i n g u a l , i n t r a m u s c u l a r , i n t r a v e n o u s , subcutaneous), such t h a t i t d i r e c t l y e n t e r s a systemic a r t e r y o r v e i n , d i s t r i b u t i o n occurs so t h a t o n l y -30% of the dose o f t h e drug reaches the l i v e r on i t s f i r s t c i r c u l a t i o n through the body. In c o n t r a s t , i f a drug i s g i v e n by a h e p a t i c r o u t e (e.g. per os. i n t r a p e r i t o n e a l , p o r t a l o r s p l e n i c v e i n i n f u s i o n ) , a b s o r p t i o n o c c u r s a c r o s s t h a t p a r t o f the GI e p i t h e l i u m d r a i n e d by t h e h e p a t i c p o r t a l system (Blaschke, 1979). In thes e cases, t h e e n t i r e absorbed dose i s exposed t o the l i v e r p r i o r t o mixing w i t h the systemic c i r c u l a t i o n and, i f h e p a t i c metabolism o c c u r s , a c e r t a i n percentage o f t h e dose w i l l be e x t r a c t e d p r i o r t o exposure t o the r e s t o f the body. Thus, f o r c e r t a i n drugs a s u b s t a n t i a l p o r t i o n o f an o r a l dose may be me t a b o l i z e d p r i o r t o the systemic c i r c u l a t i o n and s i t e o f p h a r m a c o l o g i c a l a c t i o n . T h i s p r o c e s s i s known as h e p a t i c f i r s t - p a s s metabolism or f i r s t - p a s s e f f e c t ( H a r r i s and Riegelman, 1969). 1.3 D o s e - L i n e a r i t y o f K i n e t i c s The v e l o c i t y o f a chemical r e a c t i o n can g e n e r a l l y be expressed by the equ a t i o n : dC = K C dt where C i s t h e c o n c e n t r a t i o n o f r e a c t a n t , K i s t h e k i n e t i c r a t e c o n s t a n t and n i s the o r d e r o f t h e r e a c t i o n (Holtzman, 1983). In the pharmacokinetics o f most drugs i t appears t h a t over some f i n i t e range n=l thus producing 13 an i n t e g r a t e d e q u a t i o n t h a t i s termed " l i n e a r " . I t sh o u l d be noted t h a t the use of the term " l i n e a r " i n t h i s c o n t e x t i s not t r u l y m a t h e m a t i c a l l y r i g o r o u s but i s entrenched i n pharmacokinetic l i t e r a t u r e . As w e l l , the time course o f drug c o n c e n t r a t i o n f o r many drugs cannot be expressed by a s i n g l e e x p o n e t i a l term and i s i n s t e a d equated t o a sum of s e v e r a l a p p a r e n t l y f i r s t o r d e r p r o c e s s e s (Holtzman, 1983). These " l i n e a r " models assume t h a t the pharmacokinetic parameters f o r a drug do not change when d i f f e r e n t s i z e o r m u l t i p l e doses a r e ad m i n i s t e r e d ( Sh a r g e l and Yu, 1985). However, t h i s view i s c l e a r l y flawed s i n c e many o f the pharmacokinetic p r o c e s s e s o f a b s o r p t i o n , d i s t r i b u t i o n , b i o t r a n s f o r m a t i o n and e l i m i n a t i o n are mediated by enzymatic o r c a r r i e r systems which c l e a r l y have some l i m i t a t i o n t o t h e i r c a p a c i t y . S a t u r a t i o n o f these systems l e a d s t o d e v i a t i o n from a p p a r e n t l y " l i n e a r " k i n e t i c s and, hence, the d i s p l a y o f " n o n l i n e a r " o r dose-dependent k i n e t i c s . In g e n e r a l , drugs d i s p l a y i n g dose-dependent k i n e t i c s d i s p l a y the f o l l o w i n g c h a r a c t e r i s t i c s (Shargel and Yu, 1985): 1) Drug e l i m i n a t i o n i s not a simple f i r s t - o r d e r p r o c e s s . 2) As dose i n c r e a s e s so does e l i m i n a t i o n h a l f - l i f e . 3) AUC does not i n c r e a s e p r o p o r t i o n a t e l y t o an i n c r e a s e i n dose. 4) C a p a c i t y l i m i t e d p r o c e s s e s may be a f f e c t e d , a t s a t u r a t i o n , by o t h e r drugs r e q u i r i n g t h e same sy s t e m ( s ) . 5) The composition o f m e t a b o l i t e s may be a l t e r e d as the dose i s changed. S i n c e the pharmacokinetic parameters may be a l t e r e d as a d d i t i o n a l doses a re g i v e n , p r e d i c t i o n o f drug l e v e l s a t s t e a d y - s t a t e based on data gathered from s i n g l e dose s t u d i e s i s d i f f i c u l t . Although i t i s unexpected t h a t any drug w i l l d i s p l a y " l i n e a r " k i n e t i c s over an i n f i n i t e c o n c e n t r a t i o n , range most drugs do d i s p l a y l i n e a r k i n e t i c s over a s i g n i f i c a n t range. I t i s t h e r e f o r e important t o c h a r a c t e r i z e the " l i n e a r i t y " o f k i n e t i c s o f a drug over the u s u a l t h e r a p e u t i c dose range i n o r d e r t o o p t i m i z e s a f e t y and e f f i c a c y o f drug treatment t o p a t i e n t s on m u l t i p l e dose therapy. 1.4 E f f e c t s o f Chro n i c Renal F a i l u r e on Pharmacokinetics Although the kidneys are commonly viewed as organs o f e x c r e t i o n f o r many drugs, c h r o n i c r e n a l f a i l u r e can a l t e r a l l o f the A.D.M.E. p r o c e s s e s , e i t h e r s i n g l y o r s i m u l t a n e o u s l y . The changes i n the A.D.M.E. pr o c e s s e s brought about by c h r o n i c r e n a l f a i l u r e r e f l e c t , i n many cases, the p h y s i o l o g i c a l r o l e s o f the kidney t h a t are d i s s o c i a t e d from simple e x c r e t i o n and the importance o f t h i s organ system t o homeostasis. 1.4.1 A b s o r p t i o n and B i o a v a i l a b i l i t y L i t t l e i n t e n s i v e study has been made on the e f f e c t s of c h r o n i c r e n a l f a i l u r e on drug a b s o r p t i o n . Yet many sequelae o f c h r o n i c r e n a l f a i l u r e and i t s t h e r a p y can l e a d t o changes i n the a b s o r p t i o n and b i o a v a i l a b i l i t y o f ph a r m a c e u t i c a l s . Some of the most pronounced f e a t u r e s o f the uremic syndrome are d i s p l a y e d i n the g a s t r o i n t e s t i n a l t r a c t . F e a t u r e s such as nausea, v o m i t i n g , d i a r r h e a , p a n c r e a t i t i s , and c o l i t i s are common ( H o f f s t e n and K l a h r , 1983) . These p r o c e s s e s can a l t e r the m o t i l i t y o f the G l t r a c t and t h e r e f o r e can change the exte n t o f a b s o r p t i o n o f many drugs (Riegelman and Rowland, 1973). In a d d i t i o n , the a b s o r p t i o n o f many drugs i s r e l a t e d t o the degree o f g a s t r i c a c i d i t y . P a t i e n t s w i t h c h r o n i c r e n a l f a i l u r e may have a l t e r e d g a s t r i c pH, e i t h e r r a i s e d due t o the swallowing o f urea and subsequent c o n v e r s i o n t o ammonia, or lowered due t o an i n c r e a s e d e x c r e t i o n o f hydrogen i o n i n t o the stomach. Thus drugs whose a b s o r p t i o n depends on the pH of the G l t r a c t may have an a l t e r e d b i o a v a i l a b i l i t y i n p a t i e n t s w i t h r e n a l f a i l u r e (Anderson and G r a n b e r t o g l i o , 1976). As w e l l , ammonia c o u l d have a s i g n i f i c a n t i r r i t a n t e f f e c t on the G l mucosa, which may a f f e c t both p e r m e a b i l i t y and the s u r f a c e a r e a a v a i l a b l e f o r a b s o r p t i o n , and a l s o a l t e r the a b s o r p t i o n p r o c e s s through changes i n GI m o t i l i t y . Many p a t i e n t s r o u t i n e l y take aluminium hy d r o x i d e t a b l e t s t o decrease the a b s o r p t i o n o f d i e t a r y phosphate (Lee and Marbury, 1984). I t i s w e l l known t h a t a n t a c i d s can decrease the a b s o r p t i o n o f many drugs through complexation, a l t e r a t i o n o f g a s t r i c pH, o r a d e l a y i n g a s t r i c emptying (Hurwitz, 1974; W e l l i n g , 1984). S e v e r a l r e p o r t s o f decreased f i r s t - p a s s e f f e c t i n uremia e x i s t (Balant e t a l . , 1983). Both Lowenthal e t  a l . (1974) and B i a n c h e t t i e t a l . (1976) have shown a decreased e x t e n t o f f i r s t - p a s s metabolism f o r p r o p r a n o l o l . These f i n d i n g s have, however, been c h a l l e n g e d by Wood e t a l . (1979) on the b a s i s t h a t the c o n t r o l and r e n a l f a i l u r e groups o f B i a n c h e t t i ' s study, i n p a r t i c u l a r , were not age matched. Terao and Shen (1985) have subsequently shown t h a t a c i r c u l a t i n g f r a c t i o n p r e s e n t i n uremic r a t b l o o d i n h i b i t s e x t r a c t i o n o f p r o p r a n o l o l by r a t l i v e r which lends some credence t o the e a r l i e r r e p o r t s i n man. S i m i l a r l y the e x t e n t o f f i r s t - p a s s e f f e c t f o r d-propoxyphene has been shown t o be decreased i n c h r o n i c r e n a l f a i l u r e (Gibson e t a l . . 1977). In summary, s e v e r a l p r o c e s s e s due t o the p a t h o p h y s i o l o g y and therapy o f c h r o n i c r e n a l f a i l u r e can a l t e r the r a t e and e x t e n t o f drug a b s o r p t i o n . 1.4.2 D i s t r i b u t i o n and P r o t e i n B i n d i n g The volume o f d i s t r i b u t i o n o f a drug i s a complex term which i s the r e s u l t o f such p h y s i o l o g i c a l f a c t o r s as body f l u i d pH, t i s s u e composition, plasma p r o t e i n b i n d i n g , membrane p e r m e a b i l i t y , t i s s u e b l o o d flow and c a p i l l a r i s a t i o n ( K l o t z , 1976). In somewhat s i m p l e r terms, the volume of d i s t r i b u t i o n i s an o v e r a l l r e f l e c t i o n o f d r u g - p r o t e i n b i n d i n g , drug-RBC p a r t i t i o n i n g , and t i s s u e drug uptake (Lee and Marbury, 1984). Perhaps the most n o t a b l e change i n d i s t r i b u t i o n i s the a l t e r a t i o n of the e x t e n t o f p r o t e i n b i n d i n g o f many drugs. S e v e r a l reviews have appeared on t h i s t o p i c i n c l u d i n g two n o t a b l e o l d e r reviews (Reidenberg, 1977; T i l l e m e n t e t a l . . 1978) whose f i n d i n g s have remained l a r g e l y unchanged s i n c e p u b l i c a t i o n . In g e n e r a l , the p a t i e n t w i t h c h r o n i c r e n a l f a i l u r e i s hypoalbuminemic due t o d i e t a r y p r o t e i n r e s t r i c t i o n , decreased albumin s y n t h e s i s , and s h i f t s i n t h e t o t a l body d i s t r i b u t i o n of albumin ( T i l l e m e n t e t a l . . 1978). Furthermore th e a f f i n i t y o f t h e albumin f o r drugs may be a l t e r e d due t o t h e presence o f endogenous b i n d i n g i n h i b i t o r s (e.g. f r e e f a t t y a c i d s ) , the presence of m e t a b o l i c a c i d s , and p o s s i b l y s t r u c t u r a l changes i n the albumin b i n d i n g s i t e ( s ) ( T i l l e m e n t e t a l . , 1979). In c o n t r a s t , the c o n c e n t r a t i o n o f the acute phase r e a c t a n t , a l p h a - l - a c i d g l y c o p r o t e i n (AAG, orosomucoid) has been shown t o be i n c r e a s e d i n h e m o d i a l y s i s p a t i e n t s (Henriksen e t a l . . 1982) . The changes i n p r o t e i n c o n c e n t r a t i o n and a f f i n i t y , a s s o c i a t e d w i t h r e n a l f a i l u r e , cause the f o l l o w i n g g e n e r a l p r o c e s s e s t o occur. The b i n d i n g o f a c i d i c drugs i s g e n e r a l l y decreased w h i l e t h a t o f b a s i c o r n e u t r a l drugs i s unchanged o r i n c r e a s e d (Reidenberg and Drayer, 1984) . Examples o f both abound w i t h r e p r e s e n t a t i v e examples shown by the a c i d i c drug p h e n y t o i n ( Vd i = 0 . 5 - 0 . 7 L/kg, % bound = -90 % ; Vd . = normal ' uremic 1-1.8 L/kg, % bound = 7 5 - 8 5 %) ( G i b a l d i , 1977) and wi t h the b a s i c drug d i g o x i n ( v d n o r m a i = 7 . 3 - 8 . 1 L/kg, % bound = 25 % ; V d _ . = 4.4 - 4 .7 L/kg, % bound = -17%) uremic (Jusko and Weintraub, 1974) . The i n f l u e n c e o f changes i n p r o t e i n b i n d i n g on c l e a r a n c e has been reviewed by Rowland (1984). The i n f l u e n c e o f p r o t e i n b i n d i n g changes on c l e a r a n c e depends on the a f f i n i t y o f the drug f o r t i s s u e s o u t s i d e t he e x t r a c e l l u l a r f l u i d s and on the i n t r i n s i c c l e a r a n c e o f the drug by an organ. I f unbound drug c l e a r a n c e i s low i n comparison t o organ b l o o d flow, then organ c l e a r a n c e w i l l be s e n s i t i v e t o the ex t e n t o f p r o t e i n b i n d i n g . I f , however, organ c l e a r a n c e i s h i g h then e l i m i n a t i o n becomes p e r f u s i o n r a t e - l i m i t e d and r e l a t i v e l y i n s e n s i t i v e t o the e x t e n t o f p r o t e i n b i n d i n g . C h r o n i c r e n a l f a i l u r e i s a l s o o f t e n accompanied by a severe anemia which r e s u l t s from decreased e r y t h r o p o i e t i n p r o d u c t i o n and a decreased l i f e span o f the r e d b l o o d c e l l . T h e r e f o r e , drugs which p a r t i t i o n i n t o e r y t h r o c y t e s c o u l d have t h e i r d i s t r i b u t i o n a l t e r e d i n c h r o n i c r e n a l f a i l u r e . For example, anemic p a t i e n t s demonstrate s i g n i f i c a n t l y h i g h e r plasma gentamicin l e v e l s than s u b j e c t s w i t h a normal haematocrit ( R i f f and Jackson, 1971). End-stage r e n a l f a i l u r e may a l s o a f f e c t the t i s s u e uptake of many drugs. P o s s i b l y the b e s t example o f t h i s i s w i t h d i g o x i n (Jusko and Weintraub, 1974). With d e c r e a s i n g c r e a t i n i n e c l e a r a n c e , i t was noted t h a t the myocardial/serum c o n c e n t r a t i o n r a t i o d e creases. T h i s i m p l i e s t h a t the uptake of d i g o x i n i n t o the h e a r t decreases as r e n a l f a i l u r e worsens. Thus, the p h y s i o l o g i c a l changes brought about by r e n a l f a i l u r e may s u b s t a n t i a l l y a l t e r the d i s t r i b u t i o n o f many drugs. 1.4.3 Metabolism Although the l i v e r i s commonly thought o f as the primary m e t a b o l i c organ f o r drugs, the kidney p l a y s a s i g n i f i c a n t r o l e i n the metabolism o f many endogenous substances and x e n o b i o t i c s (Gibson, 1986). The a l t e r a t i o n o f drug metabolism i n r e n a l f a i l u r e has been the s u b j e c t o f s e v e r a l r e c e n t reviews (Reidenberg, 1977; Verbeeck e t a l . . 1981; B a l a n t e t a l . . 1983; Gibson 1986). Reidenberg (1977), based on examinations o f s t u d i e s t o t h a t time, made the f o l l o w i n g g e n e r a l i z a t i o n s w i t h r e s p e c t t o r a t e s o f m e t a b o l i c drug e l i m i n a t i o n i n uremia: a) o x i d a t i v e t y pes o f r e a c t i o n s appeared t o occur a t normal o r i n c r e a s e d r a t e s ; b) r e d u c t i v e type r e a c t i o n s were slowed; c) s y n t h e t i c r e a c t i o n s (e.g. g l u c u r o n i d a t i o n , s u l p h a t i o n , g l y c i n a t i o n , a c e t y l a t i o n ) o c c u r r e d a t a p p a r e n t l y normal r a t e s d) h y d r o l y t i c r e a c t i o n s were slowed. More r e c e n t s t u d i e s (Gibson, 1986), however, suggest t h a t these g e n e r a l i z a t i o n s may be too broad s i n c e they a r e based on too l i m i t e d a spectrum o f s t u d i e s . Verbeeck e t a l . (1981) h i g h l i g h t t h e p o s s i b i l i t y o f h y d r o l y s i s and r e c i r c u l a t i o n o f i n a c t i v e c o n j u g a t e s , p a r t i c u l a r l y g l u c u r o n i d e s , which may r e s u l t i n an a p p a r e n t l y prolonged a c t i v i t y o f the pa r e n t drug. Examples of t h i s p r o c e s s may occur f o r oxazepam, lorazepam, d i f l u n i s a l , and c l o f i b r a t e (Verbeeck e t a l . . 1981). B a l a n t e t a l . (1983) demonstrate the e f f e c t s of r e n a l f a i l u r e on the k i n e t i c s o f a v a r i e t y o f b e t a b l o c k e r s and the c e p h a l o s p o r i n , cefoperazone. These a u t h o r s , however, do not r e l a t e any p r e c i s e causes of the a l t e r a t i o n s i n h e p a t i c metabolism t o the e x i s t e n c e o f r e n a l f a i l u r e . R e c e n t l y , Gibson (1986) reviewed many s t u d i e s w i t h r e s p e c t t o the e f f e c t o f r e n a l f a i l u r e on drug metabolism, both h e p a t i c and e x t r a - h e p a t i c . T h i s review p r o v i d e s a more comprehensive and updated approach t o the work of Reidenberg (1977). In summary, th e f i n d i n g s o f Gibson (1986) concur w i t h those of t h e p r e v i o u s authors (Reidenberg, 1977; Verbeeck e t a l . . 1981; B a l a n t e t a l . f 1983), i n t h a t (1) r e n a l d i s e a s e may a l t e r h e p a t i c drug metabolism and (2) t h a t the kidneys may p l a y an important r o l e i n x e n o b i o t i c metabolism. Although i t i s d i f f i c u l t t o demonstrate s p e c i f i c mechanisms c a u s i n g a l t e r a t i o n s of drug metabolism i n r e n a l f a i l u r e , s e v e r a l p o s s i b i l i t i e s e x i s t . Massive r e t e n t i o n of m e t a b o l i t e s , n o r m a l l y e x c r e t e d by the kidney, may r e s u l t i n " n e g a t i v e feedback", t h e r e b y i n h i b i t i n g the c o n v e r s i o n of the p a r e n t drug (Verbeeck, 1982; Gibson, 1986). The a c t i v i t y o f the mixed f u n c t i o n o x i d a s e system i n r a t s has been shown t o be d i m i n i s h e d i n e x p e r i m e n t a l l y induced r e n a l f a i l u r e (Gibson, 1986) but comparable f i n d i n g s i n man have not been r e p o r t e d . R e c e n t l y , Terao and Shen (1985) demonstrated t h a t a s o l u b l e f r a c t i o n o f uremic r a t b l o o d reduced th e e x t r a c t i o n o f p r o p r a n o l o l by an i s o l a t e d r a t l i v e r , thus r a i s i n g the p o s s i b i l i t y o f a c i r c u l a t i n g m e t a b o l i c i n h i b i t o r . T h i s r e s u l t may e x p l a i n f i n d i n g s by B i a n c h e t t i e t a l . (1976) and Lowenthal e t a l . (1974) of decreased c l e a r a n c e o f p r o p r a n o l o l i n uremic p a t i e n t s . I t has a l s o been demonstrated t h a t r e n a l f a i l u r e d ecreases o r g a n i c anion t r a n s p o r t i n t o the l i v e r , a l t h o u g h s i m i l a r r e s u l t s f o r o r g a n i c c a t i o n s have not been r e p o r t e d (Yates e t a l . . 1985) . 1.4.4 E l i m i n a t i o n of I n t a c t Drug and M e t a b o l i t e s Perhaps the most obvious change i n pharmacokinetics i n r e n a l f a i l u r e i s the d i m i n i s h e d e x c r e t i o n and hence i n c r e a s e d serum h a l f - l i f e of the p a r e n t drug and m e t a b o l i t e s t h a t are n o r m a l l y e x c r e t e d by the kidney. The c l e a r a n c e o f the endogenous substance, c r e a t i n i n e , a l l o w s an e s t i m a t i o n o f g l o m e r u l a r f i l t r a t i o n r a t e t h a t , f o r a number o f drugs, r e f l e c t s drug e l i m i n a t i o n ( G i b a l d i and P e r r i e r , 1982). I t i s r e c o g n i z e d , however, t h a t the k i d n e y i s a l s o capable of s e c r e t i o n , p a r t i c u l a r l y i n t h e S 3 segment of the proximal t u b u l e , as w e l l as r e s o r p t i o n a l o n g the nephron. These p r o c e s s e s may a l t e r the a c c u r a c y of k i n e t i c e s t i m a t e s based on c r e a t i n i n e c l e a r a n c e d e r i v e d g l o m e r u l a r f i l t r a t i o n r a t e . S e v e r a l authors have reviewed the e f f e c t s o f r e n a l d i s e a s e on drug e l i m i n a t i o n ( D e t t l i , 1976; Levy, 1977; Fabre and B a l a n t , 1976; Jusko, 1980; Vree e t a l . . 1983; Lee and Marbury, 1984). T h e i r approaches stem from the f a c t t h a t the o v e r a l l e l i m i n a t i o n r a t e c o n s t a n t can be E expressed as the sum o f r e n a l and non-renal e l i m i n a t i o n r a t e c o n s t a n t s . K = K + K E r e n a l non-renal and, assuming f o r most drugs t h a t K r e n a j i s a l i n e a r f u n c t i o n o f c r e a t i n i n e c l e a r a n c e , then: K E - A < C 1cr> + K n o n - r e n a l where: A = c o n s t a n t C l = c r e a t i n i n e c l e a r a n c e , c r Thus, drugs can be broken up i n t o t h r e e g e n e r a l k i n e t i c c l a s s e s ; a ) those e l i m i n a t e d s o l e l y by r e n a l r o u t e s , b) those e l i m i n a t e d s o l e l y by n o n-renal r o u t e s , and c) those e l i m i n a t e d by both r o u t e s ( D e t t l i , 1976). A p l o t o f K„ vs C l f o r each c l a s s of drugs i s shown i n £i c r F i g u r e 2: B F i g u r e 2: The D e t t l i Nomogram ( D e t t l i , 1976) Thus, i t can be seen t h a t those drugs r e l y i n g on e x c l u s i v e l y r e n a l mechanisms f o r e l i m i n a t i o n w i l l accumulate, s i n c e t h e i r h a l f - l i v e s w i l l be much prolonged. I t a l s o appears t h a t those drugs removed e x c l u s i v e l y by non-renal r o u t e s w i l l have t h e i r h a l f - l i v e s s u b s t a n t i a l l y u n a l t e r e d , however as p r e v i o u s l y d i s c u s s e d , t h i s may be an o v e r - s i m p l i f i c a t i o n . F i n a l l y , t he magnitude o f change f o r those drugs e l i m i n a t e d by both r o u t e s w i l l depend on the r e l a t i v e magnitudes of r e n a l and non-renal e l i m i n a t i o n . As w e l l as accumulation o f the pa r e n t drug, accumulation o f p o l a r m e t a b o l i t e s may a l s o o c c u r i n r e n a l f a i l u r e . T h i s phenomenon has been e x t e n s i v e l y reviewed by Verbeeck e t a l . (1981). A p p r e c i a t i o n o f t h i s i s important s i n c e accumulation o f m e t a b o l i t e s may l e a d t o a l t e r e d t h e r a p e u t i c o r t o x i c e f f e c t s i n a r e n a l l y i m p a i r e d p a t i e n t . In summary, c h r o n i c r e n a l f a i l u r e can produce s i g n i f i c a n t changes i n almost a l l p h a r m a c o k i n e t i c parameters due t o the f a c t t h a t the kidney f u l f i l l s many o t h e r p h y s i o l o g i c a l r o l e s b e s i d e s maintenance o f f l u i d and e l e c t r o l y t e b a l a n c e . 1.5 I n f l u e n c e o f Hemodialysis on Drug Removal D i a l y s i s may be d e f i n e d as the s e p a r a t i o n o f c r y s t a l l i n e substances (e.g. NaCl) from c o l l o i d a l substances (e.g. serum albumin) u t i l i z i n g d i f f e r e n c e s i n t h e i r r a t e s o f movement a c r o s s a semi-permeable membrane. Hem o d i a l y s i s i n v o l v e s p a s s i n g the p a t i e n t s b l o o d through an " a r t i f i c i a l k idney" w i t h a semi-permeable membrane around which flows a d i a l y s a t e o f s i m i l a r c o m p o s i t i o n t o normal plasma. S o l u t e s then are f r e e t o move from b l o o d t o d i a l y s a t e o r v i c e v e r s a by p a s s i v e d i f f u s i o n o r accompanying water movement ( s o l v e n t d r a g ) . In a d d i t i o n t o removing s o l u t e s from the uremic plasma, d i a l y s i s a l s o removes water from the d i a l y s i s p a t i e n t v i a u l t r a -f i l t r a t i o n . The movement of a substance a c r o s s t h e semi-permeable membrane i s i n f l u e n c e d by s e v e r a l f a c t o r s (Gibson and Nelson, 1977; Lee and Marbury, 1984). S i n c e the semipermeable membrane has d i s c r e t e pores s o l u t e shape, m o l e c u l a r s i z e and m o l e c u l a r weight s i g n i f i c a n t l y i n f l u e n c e t h e a b i l i t y o f the molecule t o pass through e a s i l y . G e n e r a l l y , h e m o d i a l y s i s i s e f f e c t i v e i n removing s o l u t e s w i t h m o l e c u l a r weights below 5000 D a l t o n s . Substances t h a t are water s o l u b l e are g e n e r a l l y removed more r e a d i l y than those t h a t are more l i p o p h i l i c . The surface' area, p o r o s i t y , and t h i c k n e s s o f the semipermeable membrane a l s o i n f l u e n c e the r a t e o f s o l u t e removal. The r a t e s of flow o f t h e b l o o d and d i a l y s a t e and t h e p r o x i m i t y of the e n t i r e system t o s i n k c o n d i t i o n s are a l s o s i g n i f i c a n t f a c t o r s i n f l u e n c i n g the r a t e o f s o l u t e movement. Drugs, as s o l u t e s i n the plasma can a l s o be removed by h e m o d i a l y s i s . The removal o f p h a r m a c e u t i c a l s by h e m o d i a l y s i s has been reviewed by many authors (Gibson e t  a l . . 1977; Maher, 1977; Gibson and Nelson, 1977; Watanabe, 1977; Lee and Marbury, 1984). Although governed by t h e same requirements as plasma s o l u t e s f o r removal by h e m o d i a l y s i s , s e v e r a l p harmacokinetic parameters can g i v e an i n d i c a t i o n o f whether a drug w i l l be d i a l y s a b l e or not (Lee and Marbury, 1984). S i n c e the e x i s t e n c e o f a c o n c e n t r a t i o n g r a d i e n t i s e s s e n t i a l as a d r i v i n g f o r c e f o r p a s s i v e d i f f u s i o n , Vd i s o f primary importance t o drug d i a l y s a b i l i t y . G e n e r a l l y , drugs w i t h Vd < 1 L/kg w i l l be d i a l y s a b l e w h i l e those w i t h Vd > 2 L/kg w i l l not. Furthermore, s i n c e o n l y f r e e drug can be removed, drugs t h a t are h i g h l y p r o t e i n bound a r e not l i k e l y t o be e x t e n s i v e l y removed by h e m o d i a l y s i s . Those drugs n o r m a l l y e x c r e t e d p r i m a r i l y by the kidney w i l l be more d i a l y s a b l e than those p r i m a r i l y e x c r e t e d by metabolism. Drugs w i t h v e r y l o n g o r v e r y s h o r t e l i m i n a t i o n h a l f - l i v e s are u s u a l l y not d i a l y s a b l e . S i n c e maximal d i a l y s e r c l e a r a n c e s are on the o r d e r o f 100 mL/min, those drugs w i t h m e t a b o l i c c l e a r a n c e s > 200 mL/min (e.g. t r i c y c l i c a n t i d e p r e s s e n t s ) a r e not d i a l y s a b l e s i n c e removal by d i a l y s i s i s rendered non-competitive by the h i g h i n t r i n s i c c l e a r a n c e . Levy (1977) s t a t e s t h a t f o r h e m o d i a l y s i s t o be a s i g n i f i c a n t c o n t r i b u t o r t o t o t a l body c l e a r a n c e of drug i t must account f o r > 30% of t o t a l body c l e a r a n c e . M a t h e m a t i c a l l y , d i a l y s i s may be t r e a t e d as any o t h e r f i r s t - o r d e r r o u t e of drug e l i m i n a t i o n . S e v e r a l authors have d e s c r i b e d the equations necessary t o d e s c r i b e drug removal by d i a l y s i s (Maher, 1977; Gibson and Nelson, 1977, Watanabe, 1977; G w i l t , 1981; Lee and Marbury, 1984). Wellhoner (1981) has extended t h e s e c a l c u l a t i o n s t o a two-compartment system. Two e x t e n s i v e reviews of drug removal by p e r i t o n e a l d i a l y s i s have a l s o r e c e n t l y appeared (Janknegt and Koks, 1984; Paton e t a l . . 1985). 1.6 1.6.1 Metoclopramide Pharmacokinetics Animal Models Animal experiments ( r a b b i t , r a t , and dog) have shown t h a t metoclopramide (MCP) i s w e l l absorbed, e x t e n s i v e l y m e t a b o l i z e d , and r a p i d l y e x c r e t e d i n t h e s p e c i e s s t u d i e d (Tunon e t a l . . 1974; Bakke and Segura, 1976; Bateman e t a l . r 1980; Tarn e t a l . . 1981). Metabolism o c c u r s v i a 4 s u l p h a t e and g l u c u r o n i d e c o n j u g a t i o n a t the N p o s i t i o n [rabb'it, dog] ( A r i t a e t a l . . 1970 ; Cowan e t a l . . 1976; Bateman e t a l . . 1978), O-demethylation, N - d e - e t h y l a t i o n and amide h y d r o l y s i s [rat, r a b b i t , dog] ( A r i t a e t a l . . 1970; Bakke and Segura, 1976; Cowan e t a l . , 1976). Peak plasma c o n c e n t r a t i o n s occur 30-120 minutes a f t e r o r a l MCP d o s i n g . E a r l y r e p o r t s (Bakke and Segura, 1976) gave the e l i m i n a t i o n h a l f - l i f e o f MCP f o l l o w i n g IV i n j e c t i o n as 20, 28, and 3 6 minutes i n t h e r a t , r a b b i t , and dog r e s p e c t i v e l y . Somewhat i n c o n t r a s t t o t h i s , Tarn and A x e l s o n (1978) demonstrated a h a l f - l i f e o f 50 minutes i n t he r a t w i t h dose-dependent changes i n ^2./2 d o s e s above 15 mg/kg. Furthermore s t u d i e s i n the r a t by K a p i l e t a l . (1984) and Tarn e t a l . (1981) suggest t h a t MCP undergoes s a t u r a b l e f i r s t - p a s s metabolism a t doses below 1 mg/kg and unusual dose-dependent k i n e t i c s due t o a p p a r e n t l y MCP induced h e p a t i c b l o o d flow changes a t doses above 15 mg/kg. Tam e t a l . (1981a) have a l s o c a r r i e d out k i n e t i c s t u d i e s i n r a t s w i t h e x p e r i m e n t a l l y induced r e n a l and h e p a t i c f a i l u r e . E x p e r i m e n t a l l y induced (CCl^) h e p a t i c f a i l u r e l e a d s t o an approximate 3 f o l d i n c r e a s e i n plasma h a l f - l i f e and area under the plasma c o n c e n t r a t i o n vs time curve (AUC). Volume of d i s t r i b u t i o n , however, was shown t o remain e s s e n t i a l l y unchanged. U r i n a r y e x c r e t i o n of i n t a c t MCP was approximately doubled i n these animals y e t t h e f o r m a t i o n o f the N-de-ethylated m e t a b o l i t e was unchanged, s u g g e s t i n g e x t r a h e p a t i c f o r m a t i o n o f t h i s substance. I n v e s t i g a t i o n s o f animals w i t h e x p e r i m e n t a l l y induced r e n a l f a i l u r e (5/6 two-step nephrectomy, b i l a t e r a l u r e t e r a l l i g a t i o n , o r u r a n y l n i t r a t e ) showed a t l e a s t a t w o - f o l d i n c r e a s e i n plasma h a l f - l i f e and AUC w i t h a p r o p o r t i o n a l decrease i n t o t a l body c l e a r a n c e . Volume o f d i s t r i b u t i o n was s l i g h t l y decreased i n these animals. Although t h e s e i n v e s t i g a t o r s p o s t u l a t e d d i m i n i s h e d e x t r a h e p a t i c metabolism as the mechanism f o r the a l t e r a t i o n s seen i n r e n a l f a i l u r e , t h i s has been r u l e d out by K a p i l e t a l . (1984). A more l i k e l y mechanism i s the decrease i n h e p a t i c metabolism secondary t o r e n a l f a i l u r e (Bateman e t a l . . 1981; K a p i l e t a l . . 1984) 1.6.2 Human S t u d i e s S e v e r a l s t u d i e s have been completed on the pha r m a c o k i n e t i c s and b i o a v a i l a b i l i t y o f MCP i n normal, h e a l t h y v o l u n t e e r s . The k i n e t i c s t u d i e s have tended t o focus e i t h e r on the doses used i n cancer chemotherapy (1-2 mg/kg as a s h o r t i n f u s i o n ) ( T a y l o r e t a l . , 1984; Bryson e t a l . , 1985; S a i l e r e t a l . , 1985) or on lower doses (5-50 mg) ( G r a f f n e r e t a l . , 1979; Schuppan e t a l . . 1979; Bateman e t a l . f 1980; Ross-Lee e t a l . , 1981; Bateman e t a l . . 1981; Block e t a l . . 1981; Bateman, 1983). While the more r e c e n t "high-dose" chemotherapy s t u d i e s have been g e n e r a l l y w e l l done, u n f o r t u n a t e l y , many o f the e x i s t i n g "low-dose" s t u d i e s s u f f e r from a n a l y t i c a l and/or m e t h o d o l o g i c a l problems t h a t c a s t some degree o f doubt on t h e i r f i n d i n g s . B a s i c a l l y these d e f i c i e n c i e s f a l l i n t o t h r e e g e n e r a l c a t a g o r i e s : (1) poor assay s e n s i t i v i t y / s e l e c t i v i t y (Schuppan e t a l . . 1979; Bateman e t a l . , 1980) (2) the use of a t a b l e t o r c a p s u l e as the o r a l r e f e r e n c e dosage form i n b i o a v a i l a b i l i t y assessments (Schuppan e t  a l . , 1979; G r a f f n e r e t a l . f 1979; Bateman e t a l . . 1980; Ross-Lee e t a l . , 1981) (3) f a i l u r e t o compare equal o r a l and IV doses (Schuppan e t a l . . 1979; G r a f f n e r e t a l . , 1979; Block e t a l . . 1981). The f a i l u r e o f many of the p r e v i o u s assay methods t o be s e n s i t i v e and s e l e c t i v e has r e s u l t e d i n s e v e r a l problems. The most s i g n i f i c a n t o f these i s the l a c k o f a b i l i t y t o sample plasma l o n g enough a f t e r d o s i n g t o produce an a c c u r a t e e s t i m a t e of the t r u e b i o l o g i c a l h a l f - l i f e . G i b a l d i and Weintraub (1971) have shown t h a t t r u n c a t i o n of the sampling i n t e r v a l can l e a d t o an u n d e r e s t i m a t i o n of the b i o l o g i c a l h a l f - l i f e . The i n a c c u r a c y i n h a l f - l i f e d e t e r m i n a t i o n has l e d t o c l a i m s of dose-dependency o f MCP k i n e t i c s (Bateman e t a l . , 1980; Bateman, 1983) which may be a r t i f a c t u a l . The use of a t a b l e t or c a p s u l e as the o r a l r e f e r e n c e dosage form i n b i o a v a i l a b i l i t y s t u d i e s can be i n a p p r o p r i a t e i n some i n s t a n c e s s i n c e d i s i n t e g r a t i o n and d i s s o l u t i o n r a t e s can s u b s t a n t i a l l y a l t e r b i o a v a i l a b i l t i y (Riegelman and Rowland, 1973). A more a p p r o p r i a t e dosage form i s the commercially a v a i l a b l e o r a l s o l u t i o n . A lthough i t i s p o s s i b l e t o determine b i o a v a i l a b i l t i y from unequal o r a l and IV doses, such a d e t e r m i n a t i o n i s based on the e x i s t e n c e of l i n e a r k i n e t i c s over the dose range i n q u e s t i o n . P r i o r t o 1984, no such d e t e r m i n a t i o n had been made, i n f a c t the evidence from animal models ( K a p i l e t a l . , 1984; Tam e t a l . , 1981) was q u i t e t o the c o n t r a r y . R e c e n t l y , Wright e t a l . (1984) have demonstrated l i n e a r k i n e t i c s i n the range of 20 - 100 mg. L i n e a r k i n e t i c s have a l s o been observed i n the high-dose cancer chemotherapy t r i a l s (Bryson e t a l . . 1985). These dosages are , however, cover a d i f f e r e n t range from those examined i n t h e f o l l o w i n g study. In g e n e r a l , MCP appears t o be r a p i d l y absorbed from th e G l w i t h a s i g n i f i c a n t f i r s t - p a s s e f f e c t (Bateman e t a l . . 1979; Ross-Lee e t a l . . 1981). MCP appears t o be w i d e l y d i s t r i b u t e d i n man w i t h volume of d i s t r i b u t i o n r a n g i n g from 2.2 - 3.4 L/kg ( H a r r i n g t o n e t a l . . 1983). MCP i s -40 % bound t o plasma p r o t e i n s p a r t i c u l a r l y t o AAG (Webb e t a l . . 1986). In man, MCP i s predominantly 4 m e t a b o l i z e d t o the N -sulphonate (-32-40% o f IV or o r a l dose) (Bateman e t a l . , 1980; Teng e t a l . . 1977) as w e l l 4 as a minor (<5%) c o n t r i b u t i o n from the N - g l u c u r o n i d e . Approximately 25 % of the dose i s e x c r e t e d as i n t a c t drug (Teng e t a l . , 1977). T o t a l body c l e a r a n c e i s r e l a t i v e l y h i g h (11.61 mL/min/kg) ( H a r r i n g t o n e t a l . . 1983) w i t h r e n a l c l e a r a n c e a c c o u n t i n g f o r about 20 % of t h i s v a l u e . E l i m i n a t i o n h a l f - l i f e ranges from 2.6 - 5.1 hours ( H a r r i n g t o n e t a l . , 1983) and c l a i m s of dose dependency have been made ( G r a f f n e r e t a l . . 1979; Bateman, 1983). Given the pharmacokinetic i n f o r m a t i o n a v a i l a b l e about MCP i n normal human v o l u n t e e r s i t was unexpected t h a t t h e k i n e t i c s s h o u l d be s i g n i f i c a n t l y a l t e r e d i n p a t i e n t s w i t h r e n a l f a i l u r e . However, s e v e r a l r e p o r t s t o Lancet showed a h i g h e r i n c i d e n c e of s i d e e f f e c t s i n uremic p a t i e n t s g i v e n MCP ( C a r a l p s , 1979; Bateman and Davies, 1979; Bateman and Gokal, 1980). T h i s was l a t e r a t t r i b u t e d t o an unexpectedly l a r g e decrease i n t o t a l body c l e a r a n c e of MCP i n uremic p a t i e n t s (Bateman e t a l . . 1981). R e c e n t l y another study (Lehmann e t a l . . 1985) has been completed i n p a t i e n t s w i t h r e n a l f a i l u r e . These s t u d i e s have shown a t l e a s t a t w o - f o l d decrease i n t o t a l body c l e a r a n c e w i t h a p r o p o r t i o n a l i n c r e a s e i n plasma e l i m i n a t i o n h a l f - l i f e . P r e l i m i n a r y evidence suggests t h a t h e m o d i a l y s i s (Bateman e t a l . . 1981, Lehmann e t a l . 1985) and p e r i t o n e a l d i a l y s i s ( B e r a r d i e t a l . . 1986) are i n e f f e c t i v e a t removing MCP from the body. T h i s i s p r o b a b l y the r e s u l t of the l a r g e volume o f d i s t r i b u t i o n of MCP. No mechanism has been proven t o be r e s p o n s i b l e f o r the unexpected changes i n MCP k i n e t i c s shown by uremic p a t i e n t s . Lehmann e t a l . (1986) have suggested a c i r c u l a t i n g m e t a b o l i c i n h i b i t o r but t h i s has not been s u b s t a n t i a t e d . 2. EXPERIMENTAL 2.1 M a t e r i a l s and S u p p l i e s 2.1.1 Chemicals The f o l l o w i n g were s u p p l i e d by A.H. Robins Canada Inc., M o n t r e a l , Quebec: 4-amino-5-chloro-2-methoxy-N-(2-diethyl aminoethyl) benzamide monohydrochloride monohydrate (MCP.HC1.H20) (Lot Nos. A105 and F058), MCP.HCl 5 mg/mL ( R e g l a n R I n j e c t a b l e , 2 mL Ampule) (Lot No. 84637), MCP.HCl Syrup lmg/mL ( R e g l a n R , 100 mL b o t t l e ) (Lot No. 8474), MCP.HCl H 20 T a b l e t s 10 mg (Reglan R) (Lot No. 84707). M a p r o t a l i n e . H C l (MAP HCl) (N-methyl -9-10-ethanoanthracene-9(10H) propanamide H y d r o c h l o r i d e ) Lo t A11663096472-0 was s u p p l i e d by C i b a Pharmaceuticals, M i s s i s s a u g a , O n t a r i o . 2.1.2 Reagents ACS reagent grade Sodium Hydroxide p e l l e t s were o b t a i n e d from F i s h e r S c i e n t i f i c Co., F a i r Lawn , NJ, U.S.A.. ACS reagent grade H y d r o c h l o r i c A c i d 37% was o b t a i n e d from American S c i e n t i f i c and Chemical, S e a t t l e , WA, U.S.A.. Ammonia S o l u t i o n Strong 27% was o b t a i n e d from M a l l i n c k r o d t Inc., S t . L o u i s , MI, U.S.A.. H e p t a f l u o r o b u t y r i c Anhydride and T r i e t h y l a m i n e Sequanal Grade were o b t a i n e d from P i e r c e Chemical Co., Rockford, IL, U.S.A.. 2.1.3 S o l v e n t s Benzene and t o l u e n e ( d i s t i l l e d i n g l a s s ) were o b t a i n e d from Caledon L a b o r a t o r i e s Inc., Georgetown, Ont.. D e i o n i z e d water was produced on s i t e v i a a M i l l i - R O System, M i l l i p o r e Corp., Bedford, MA., U.S.A.. Methanol ACS reagent grade and acetone ACS reagent grade were o b t a i n e d from BDH Chemicals, Toronto, O n t a r i o . 2.1.4 Gases N i t r o g e n U.S.P.and M e d i c a l A i r were o b t a i n e d from Union C a r b i d e Canada L t d . , Toronto, O n t a r i o . Hydrogen UHP and Argon/Methane (95:5) were o b t a i n e d from Matheson Gas Products Canada L t d ; Edmonton, A l b e r t a . 2.1.5 S u p p l i e s f o r Human Experiments Intravenous drug a d m i n i s t r a t i o n was made through a R TM s t e r i l e A r g y l e Venocut i n f u s i o n s e t (19 gauge needle) o b t a i n e d from Sherwood M e d i c a l , S t . L o u i s , MI, U.S.A.. A B u t t e r f l y R - 1 9 INT cannula (Abbott I r e l a n d , S l i g o , R e p u b l i c o f I r e l a n d ) was implanted i n the c o n t r a l a t e r a l arm t o f a c i l i t a t e b l o o d sampling. G l a s s 1 mL (Glaspak ), p l a s t i c 1 mL and 3 mL s y r i n g e s , 22 and 25 gauge needles, and l u e r adapters were o b t a i n e d from Becton-Dickson Canada, M i s s i s s a u g a , O n t a r i o . U r i n e samples were c o l l e c t e d i n Whirl-pak bags (AHS Canada, Richmond, B.C.). Whole b l o o d was c o l l e c t e d i n t o h e p a r i n i z e d v a c u t a i n e r tubes ( V a c u t a i n e r Systems, R u t h e r f o r d , NJ, U.S.A.). F o l l o w i n g c e n t r i f u g a t i o n the plasma was s t o r e d f r o z e n i n s t e r i l e Pyrex tubes (Corning G l a s s Works, Corning, NY, U.S.A.). 2.2 Equipment A model 584OA Hewlett-Packard gas chromatograph 6 3 equipped w i t h a N i e l e c t r o n c a p t u r e d e t e c t o r (ECD), a model 18850A GC t e r m i n a l and i n t e g r a t o r , and a packed column compatible model 18835B c a p i l l a r y i n l e t system, Hewlett Packard Co., Avondale, PA, U.S.A.; a bonded phase fuse d s i l i c a c a p i l l a r y column (5% phenyl methyl s i l i c o n e s t a t i o n a r y phase, c r o s s - l i n k e d ; f i l m t h i c k n e s s 0.52 um, phase r a t i o 150, column I.D. 0.31 mm, column l e n g t h 25m), Hewlett-Packard Co., Palo A l t o , CA, U.S.A.; v o r t e x - t y p e R R mixer (Vortex-Genie ), i n c u b a t i o n oven (Isotemp , model 350), F i s h e r Accumet pH meter Model 62 0, water bath w i t h temperature c o n t r o l , (Haake DI model), F i s h e r S c i e n t i f i c I n d u s t r i e s , S p r i n g f i e l d , IL, U.S.A.; IEC Model 2K C e n t r i f u g e , Damon/IEC d i v i s i o n , Needham Hts., MA, U.S.A.; r o t a t i n g - t y p e tube mixer (Labquake , model 415-110), L a b i n d u s t r i e s , Berkeley, CA, U.S.A.; 15 mL Pyrex c u l t u r e tubes w i t h T e f l o n l i n e d screw caps, Canlab, Vancouver, B.C. 2.3 P r e p a r a t i o n o f s o l u t i o n s 2.3.1 Metoclopramide.HCl Approximately 11.81 mg o f MCP.HC1.H20 ( e q u i v a l e n t t o ~10 mg of MCP f r e e base) was a c c u r a t e l y weighed, t r a n s f e r r e d t o a 100 mL v o l u m e t r i c f l a s k and d i s s o l v e d i n d e i o n i z e d water. A volume, (0.2 mL), o f t h i s s o l u t i o n was d i l u t e d t o 100 mL i n a v o l u m e t r i c f l a s k w i t h d e i o n i o n i z e d water. The f i n a l working s t o c k s o l u t i o n was produced by t a k i n g a 10 mL a l i q u o t o f the second s o l u t i o n and d i l u t i n g t h i s i n a 50 mL v o l u m e t r i c w i t h d e i o n i z e d water. The c o n c e n t r a t i o n o f the f i n a l working s t o c k s o l u t i o n was -0.04 ug/mL. 2.3.2 M a p r o t a l i n e (MAP).HCL Approximately 11.31 mg o f MAP HCl ( e q u i v a l e n t t o -10 mg o f MAP f r e e base) was a c c u r a t e l y weighed and t r a n s f e r r e d t o a 100 mL v o l u m e t r i c f l a s k and d i s s o l v e d i n d e i o n i z e d water. A volume, 0.2 mL, was then d i l u t e d t o 50 mL w i t h d e i o n i z e d water i n a v o l u m e t r i c f l a s k . The c o n c e n t r a t i o n o f t h i s working s o l u t i o n was -0.4 ug/mL. 2.3.3 Reagent S o l u t i o n s H y d r o c h l o r i c A c i d 1 N was prepared by d i l u t i n g 8.3 mL ACS reagent grade c o n c e n t r a t e d HCl (37%) t o 100 mL w i t h d e i o n i z e d water i n a v o l u m e t r i c f l a s k . Sodium Hydroxide (NaOH) 1 N and 5 N s o l u t i o n s were prepared by d i s s o l v i n g 4 and 20 g, r e s p e c t i v e l y , of NaOH p e l l e t s i n d e i o n i z e d water i n 100 mL v o l u m e t r i c f l a s k s . Ammonium Hydroxide 4% was prepared by d i l u t i n g 13.3 mL o f Strong Ammonia s o l u t i o n (30%) t o 100 mL w i t h d e i o n i z e d water i n a v o l u m e t r i c f l a s k . T r i e t h y l a m i n e , 0.0125 M i n t o l u e n e , s o l u t i o n was prepared by d i l u t i n g 0.125 mL t r i e t h y l a m i n e t o 100 mL w i t h t o l u e n e i n a v o l u m e t r i c f l a s k . Four o r f i v e NaOH p e l l e t s were then added t o the s o l u t i o n . 2.4 Sample E x t r a c t i o n procedure 2.4.1 B i o l o g i c a l F l u i d E x t r a c t i o n The method used i s i d e n t i c a l t o t h a t developed by Riggs e t a l . (1983) and i s o u t l i n e d i n Scheme 1. Normal o r uremic plasma, 0.1 - 0.5 mL, o r 0.01 t o 0.10 mL of u r i n e , • c o n t a i n i n g MCP f o l l o w i n g d o s i n g , were added t o a R c l e a n Pyrex tube c o n t a i n i n g 0.50 mL 1 N NaOH, 0.2 mL MAP i n t e r n a l (0.4 ug/mL) standard s o l u t i o n . The tubes were then made up t o a volume o f 2.2 mL w i t h d i s t i l l e d water. F o l l o w i n g the a d d i t i o n o f 6 mL benzene the tubes were capped, w i t h T e f l o n - l i n e d caps, and r o t a t e d f o r 20 minutes on a r o t a t i n g r a c k (Labquake ) t o e x t r a c t the metoclopramide and ma p r o t a l i n e . A f t e r c e n t r i f u g a t i o n a t 2300 g f o r 2 X 5 minutes the o r g a n i c phase was removed and b a c k - e x t r a c t e d u s i n g 2 mL of 1 N HCl then r o t a t e d f o r 2 0 minutes on a r o t a t i n g rack. F o l l o w i n g c e n t r i f u g a t i o n f o r 5 minutes (@ 2300 g) the o r g a n i c l a y e r was a s p i r a t e d and d i s c a r d e d (water vacuum a s p i r a t o r ) . The remaining aqueous l a y e r was washed t w i c e w i t h 4 mL of benzene, which were subsequently a s p i r a t e d . The remaining aqueous l a y e r was a l k a l i n i z e d w i t h 0.5 mL 5 N NaOH and then e x t r a c t e d f o r 20 minutes f o l l o w i n g the a d d i t i o n o f 6 mL benzene. F o l l o w i n g c e n t r i f u g a t i o n (5 min @ 2300 g ) , 5 mL of the o r g a n i c l a y e r was removed and d r i e d under a g e n t l e flow o f n i t r o g e n i n a 40 °C water bath. The n i t r o g e n d r i e d r e s i d u e s were then d e r i v a t i z e d as f o l l o w s p r i o r t o GC-ECD a n a l y s i s . 2.4.2 D e r i v a t i v e Formation The n i t r o g e n d r i e d r e s i d u e was r e c o n s t i t u t e d w i t h 800 uL of 0.0125 M T r i e t h y l a m i n e i n t o l u e n e . F o l l o w i n g r e c o n s t i t u t i o n 2 0 uL of h e p t a f l u o r o b u t y r i c anhydride were added and the samples b r i e f l y v o r t e x e d t o ensure complete mixing. The samples were then incubated a t 55°C f o r EXTRACTION PROCEDURE Blank plasma s p i k e d w i t h MCP s t a n d a r d s o l u t i o n s . d i s c a r d aqueous l a y e r Plasma samples (0.2-0.5 mL) o r u r i n e (0.01-0.5 mL) from normal/uremic s u b j e c t s . 0.5 mL IN NaOH, 0.2 mL 0.4 mcg/mL M a p r o t a l i n e , 6 mL benzene, mix, 20 min c e n t r i f u g e , 10 min Org a n i c l a y e r d i s c a r d o r g a n i c l a y e r wash t w i c e w i t h 4 mL benzene Aqueous d i s c a r d aqueous l a y e r 2 mL IN HCl, mix, 20. min c e n t r i f u g e , 5 min .ayer 0.5 mL 5N NaOH, 6 mL benzene mix, 20 min c e n t r i f u g e , 5 min Organic l a y e r evaporate t o dryness under n i t r o g e n @ 40 °C. 0.8 mL 0.125 M t r i e t h y l a m i n e i n t o l u e n e , 20 uL HFBA, d e r i v a t i z e f o r 1 hour @ 65°C. c o o l t o room temperature. 0.5 mL H2O, v o r t e x , 10 sec. 0.5 mL NH4OH, v o r t e x , 10 sec. c e n t r i f u g e , 1 min. T r a n s f e r o r g a n i c l a y e r t o v i a l s I n j e c t i n t o GC (2 uL) Scheme 1: E x t r a c t i o n Procedure (Riggs e t a l . . 1983) 1 hour. F o l l o w i n g i n c u b a t i o n the tubes were allowed t o c o o l t o room temperature, a t which time the excess HFBA reagent was h y d r o l y z e d by the a d d i t i o n o f 0.5 mL d i s t i l l e d water and v o r t e x i n g f o r 10 seconds. The excess a c i d was then n e u t r a l i z e d by the a d d i t i o n o f 0.5 mL 4% NH4OH and v o r t e x i n g f o r 10 seconds f o l l o w e d by c e n t r i f u g a t i o n (@ 2300 g) f o r 1 minute. The o r g a n i c l a y e r was then immediately t r a n s f e r r e d t o c l e a n autosampler v i a l s from which 2 uL were i n j e c t e d f o r GC-ECD a n a l y s i s . 2.5 Standard Curve P r e p a r a t i o n f o r Fused S i l i c a C a p i l l a r y GC-ECD A n a l y s i s . Volumes of 0.05, 0.1, 0.2, 0.4, 0.6, amd 0.8 mL o f MCP HCL s t o c k s o l u t i o n (0.04 ug/mL) were p i p e t t e d i n t o c l e a n Pyrex tubes c o n t a i n i n g 0.2 mL blank human plasma, 0.2 mL MAP.HCl s t o c k s o l u t i o n (0.4 ug/mL), and 0.5 mL 1 N NaOH. Each tube was then made up t o a volume of 2.2 mL wi t h d i s t i l l e d water and e x t r a c t e d and d e r i v a t i z e d as i n S e c t i o n s 2.4.1 and 2.4.2. 2.6 C a p i l l a r y GC-ECD 2.6.1 GC-ECD Parameters The parameters f o r the GC-ECD system are as f o l l o w s : I n j e c t i o n temperature 2 60 °C; i n i t i a l column temperature 205 °C; d e t e c t o r (ECD) temperature 350 °C; c a r r i e r gas (Hydrogen) flow 30 mL/min; c a r r i e r gas (Argon-Methane 95:5) flow r a t e 60 mL/min; i n l e t p r e s s u r e 10 p . s . i . ; a t t e n u a t i o n 2 6; c h a r t speed 0.4 cm/min; s l o p e s e n s i t i v i t y 0.15 - 0.4; v a l v e open time 0.1 min, v a l v e c l o s e d time 1.75 min.; r a t e o f temperature i n c r e a s e 4 °C/min a f t e r 0.81 minutes. 2.6.2 A p p l i c a t i o n of Assay t o Uremic Plasma The a p p l i c a b i l i t y of the assay method had p r e v i o u s l y been shown t o human plasma and u r i n e samples, as w e l l as sheep plasma, a m n i o t i c f l u i d , t r a c h e a l f l u i d and u r i n e . However, the a b i l i t y o f the assay t o q u a n t i f y MCP i n the presence o f the components of uremic serum was unknown. A s e r i e s o f b l a n k plasma samples were drawn from s e v e r a l uremic v o l u n t e e r s and a l i q u o t s of 150, 200, 250, and 500 uL were e x t r a c t e d and d e r i v a t i z e d as o u t l i n e d i n s e c t i o n s 2.4.1 and 2.4.2 t o determine whether any component of the b l ank uremic plasma would i n t e r f e r e w i t h the d e t e c t i o n and q u a n t i t a t i o n of e i t h e r MCP or MAP. 2.7 Pharmacokinetic S t u d i e s i n Normal and Uremic Humans. 2.7.1 Experimental P r o t o c o l i n Normal, Hea l t h y V o l u n t e e r s S i x male, non-smoking v o l u n t e e r s gave informed, w r i t t e n consent p r i o r t o the i n i t i a t i o n o f the study. A l l v o l u n t e e r s were h e a l t h y as ass e s s e d by a p h y s i c a l examination and by standar d h e m a t o l o g i c a l and b i o c h e m i c a l l a b o r a t o r y t e s t s . More s p e c i f i c a l l y none showed, or had p r i o r h i s t o r y o f , any abnormality of h e p a t i c f u n c t i o n , (as demonstrated by SGOT, SGPT, o r ALK PHOS measurements), or r e n a l f u n c t i o n (as demonstrated by BUN, serum c r e a t i n i n e , and c r e a t i n i n e c l e a r a n c e ) . A l l s u b j e c t s were f a s t e d f o r 12 hours p r i o r t o d o s i n g and f o r 4 hours f o l l o w i n g drug a d m i n i s t r a t i o n . A l l v o l u n t e e r s were i n s t r u c t e d t o a v o i d o t h e r m e d i c a t i o n s , i n c l u d i n g o v e r - t h e - c o u n t e r m e d i c a t i o n s , f o r one week p r i o r t o the study and were a l s o r e q u i r e d t o a b s t a i n from a l c o h o l f o r 48 hours p r i o r t o and d u r i n g the study. The study was conducted on a four-way c r o s s o v e r b a s i s . A l l v o l u n t e e r s r e c e i v e d a 10 mg MCP IV dose (Reglan I n j e c t a b l e , A.H. Robins Canada Inc., Montreal, Que), a 5 and 20 mg dose of MCP i n o r a l s o l u t i o n form (Reglan , A.H. R o b i n s ) . Three v o l u n t e e r s then r e c e i v e d a 10 mg dose o f MCP o r a l s o l u t i o n w h i l e the o t h e r t h r e e v o l u n t e e r s r e c e i v e d a 10 mg MCP dose as an o r a l t a b l e t (Reglan , A.H. R o b i n s ) . A l l drug a d m i n i s t r a t i o n s were s e p a r a t e d by a t l e a s t one week t o a l l o w f o r complete drug washout. On a study day, an i n d w e l l i n g cannula ( B u t t e r f l y - 1 9 INT, Venisystems, Abbott I r e l a n d Ltd.) was p l a c e d i n a forearm v e i n p r i o r t o drug a d m i n i s t r a t i o n t o f a c i l i t a t e b l o o d sampling, a blank b l o o d sample taken and the patency o f the cannula maintained throughout the experiment u s i n g h e p a r i n i z e d s a l i n e (50 U/mL). On the day o f the IV a d m i n i s t r a t i o n , another cannula was implanted i n the forearm c o n t r a l a t e r a l t o the sampling cannula. The 10 mg MCP dose was then g i v e n as a s h o r t IV i n f u s i o n over 3.5 minutes u s i n g a Harvard Model 944 i n f u s i o n pump ( M i l l i s , MA). O r a l drug a d m i n i s t r a t i o n was accompanied by ~200 mL of water. Blood samples (5 mL) were taken a t -5, 2, 4, 6, 10, 20, 40, and 60 minutes, and 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 24, 48, and 72 hours f o l l o w i n g IV drug a d m i n i s t r a t i o n . F o l l o w i n g o r a l drug a d m i n i s t r a t i o n , b l o o d samples (5 mL) were drawn a t 15, 30, 45, and 60 minutes, and 1.5, 2, 3, 5, 6, 8, 10, 12, 14, 16, 24, 48, and 72 hours. Blood was drawn from the cannula, a f t e r removal o f the h e p a r i n i z e d s a l i n e , i n t o 10 mL g l a s s V a c u t a i n e r tubes c o n t a i n i n g l i t h i u m h e p a r i n ( V a c u t a i n e r , V a c u t a i n e r Systems, R u t h e r f o r d , NJ, U.S.A.). The plasma was sep a r a t e d by c e n t r i f u g a t i o n , p l a c e d i n f r e s h g l a s s (Pyrex ) tubes w i t h screw-on T e f l o n l i n e d caps, and f r o z e n u n t i l a n a l y s i s . On a l l o c c a s i o n s , a t o t a l u r i n e c o l l e c t i o n f o r 72 hours, a t h o u r l y i n t e r v a l s f o r the f i r s t 12 hours, was made. U r i n e was c a r e f u l l y gathered i n p l a s t i c Whirl-pak bags, the volume and pH immediately measured, and an a l i q u o t s t o r e d , f r o z e n u n t i l a n a l y s i s . 6 Normal, healthy volunteers well matched for age, height, and weight -Fasted 12 h prior to and for the f i rst 4h post-dose -No medications for 1 week prior to or during study -No alcohol 48 h prior to or during study n=6 5 mg MCP oral solution n=6 10 mg MCP IV bolus n=3 10 mg MCP oral solution n=3 10 mg MCP tablet n=6 20 mg MCP oral solution Blood and urine sampled for 72 h Electron-capture gas-c iromatographic analysis Scheme 2: Study P r o t o c o l i n Normal Healthy V o l u n t e e r s 2.7.2 Q u a n t i t a t i v e A n a l y s i s i n Normals Plasma samples 0.2-0.5 mL were e x t r a c t e d and d e r i v a t i z e d as d e s c r i b e d i n S e c t i o n s 2.4.1 and 2.4.2. M a p r o t a l i n e HCl (0.4 ug/mL) was used as the i n t e r n a l s t a n d a r d . Each sample was measured i n d u p l i c a t e . Each d u p l i c a t e was i n j e c t e d (2 uL) tw i c e i n t o t h e ECD-GC. Q u a n t i t a t i v e d e t e r m i n a t i o n o f MCP was made by f i t t i n g the a r e a - r a t i o s o f the HFB d e r i v a t i v e s o f MCP/MAP t o t h e standard curve r e g r e s s i o n l i n e (area r a t i o MCP/MAP vs MCP c o n c e n t r a t i o n ) . Standard curve samples were e x t r a c t e d , d e r i v a t i z e d , and chromatographed on the same day as the v o l u n t e e r samples. The study i n normals i s summarized i n Scheme 2. 2.7.3 Experimental P r o t o c o l f o r Uremic V o l u n t e e r s E i g h t p a t i e n t s , 7 male and 1 female, w i t h severe r e n a l impairment ( c r e a t i n i n e c l e a r a n c e < 10 mL/min) and on maintenance h e m o d i a l y s i s were s t u d i e d . F o l l o w i n g a p p r o v a l o f the study p r o t o c o l by the Human E t h i c s Committee o f the U n i v e r s i t y o f B r i t i s h Columbia, a l l p a t i e n t s gave informed, w r i t t e n consent. V a l u e s f o r s t a n d a r d h e m a t o l o g i c a l and b i o c h e m i c a l t e s t s , taken as p a r t o f the r o u t i n e c l i n i c a l m o n i t o r i n g o f these p a t i e n t s , were recorded p r i o r t o drug a d m i n i s t r a t i o n . A l l p a t i e n t s f a s t e d f o r 12 hours p r i o r t o drug a d m i n i s t r a t i o n and f o r a t l e a s t 1 hour a f t e r drug a d m i n i s t r a t i o n . The uremic s u b j e c t s c o n t i n u e d any me d i c a t i o n s r e q u i r e d f o r therapy (see Appendix), however, no i n t e r f e r e n c e was noted i n the metoclopramide assay from any of these substances. The uremic p a t i e n t s r e c e i v e d a 10 mg IV dose o f MCP on two s e p a r a t e o c c a s i o n s . The f i r s t drug a d m i n i s t r a t i o n o c c u r r e d 24 hours p r i o r t o a d i a l y s i s s e s s i o n . The dose was g i v e n by a s h o r t IV i n f u s i o n , u s i n g a Harvard Model 944 i n f u s i o n pump, over 3.5 minutes. Blood samples, 1 mL, were taken from an i n d w e l l i n g cannula ( B u t t e r f l y - 1 9 - I N T R , Venisystems, Abbott I r e l a n d Ltd.) i n t o a g l a s s 1 mL t u b e r c u l i n s y r i n g e (Glaspak, Becton and Dickson, R u t h e r f o r d NJ, U.S.A,) and pr o c e s s e d as o u t l i n e d f o r t he normal v o l u n t e e r s (see S e c t i o n 2.7.1). Blood samples were drawn a t -15, 5, 15, 30, 45, and 60 minutes, and 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours f o l l o w i n g drug a d m i n i s t r a t i o n and a t h a l f - h o u r l y i n t e r v a l s from the d i a l y s e r a r t e r i a l and venous l i n e s f o r the d u r a t i o n o f h e m o d i a l y s i s . F o l l o w i n g a p e r i o d o f a t l e a s t one week, t o a l l o w f o r complete drug washout, the uremic p a t i e n t s were g i v e n a second 10 mg IV dose 1 hour p r i o r t o d i a l y s i s . Blood samples were taken a t -15, 5, 15, 30, 45, and 60 minutes, then h a l f - h o u r l y from the d i a l y s e r a r t e r i a l and venous l i n e s d u r i n g d i a l y s i s , and then a t 5, 8 Uremic volunteers (creat in ine clearance < 10 mL/min) on hemodialysis 3 times per week n=8 n=7 n = l 10 mg IV MCP 24 h p r i o r to hemodialysis plasma sampled for 24 h and during d i a l y s i s 10 mg IV MCP 1 h p r io r to hemodialysis plasma sampled for 24 h ( i n c i . d i a l y s i s ) 10 mg IV MCP 16 days post- t ransplant 10 mg V MCP 3 months post- t ransplant plasma and ur ine sampled for 24 h Electron-capture gas-chromatographic analys is Scheme 3: Study P r o t o c o l i n Uremic P a t i e n t s and Kidney T r a n s p l a n t R e c i p i e n t 6, 8, 10, 12, and 24 hours. Again, t h e b l o o d samples were p r o c e s s e d as f o r the normal h e a l t h y v o l u n t e e r s (see S e c t i o n 2.7.1). 2.7.4 Q u a n t i t a t i v e Plasma A n a l y s i s i n Uremic P a t i e n t s A volume, 0.1 - 0.3 mL, o f the plasma samples were e x t r a c t e d and d e r i v a t i z e d as p r e v i o u s l y o u t l i n e d (see S e c t i o n s 2.4.1 and 2.4.2). M a p r o t a l i n e HCl (0.4 ug/mL) was used as the i n t e r n a l standard. Each sample was measured i n d u p l i c a t e and each d u p l i c a t e was i n j e c t e d t w i c e , 2 uL, i n t o the ECD-GC f o r a n a l y s i s . Q u a n t i t a t i o n was made by f i t t i n g the area r a t i o s f o r t he HFB d e r i v a t i v e s o f MCP/MAP t o t h e sta n d a r d curve r e g r e s s i o n l i n e (area r a t i o MCP/MAP vs MCP c o n c e n t r a t i o n ) . Standard curve samples were e x t r a c t e d , d e r i v a t i z e d , and chromatographed on the same day as t h e v o l u n t e e r samples. The study i n uremics i s summarized i n Scheme 3. 2.7.5 E x perimental P r o t o c o l f o r the Kidney T r a n s p l a n t R e c i p i e n t Subsequent t o the f i r s t a d m i n i s t r a t i o n o f MCP t o a uremic male v o l u n t e e r (BM), t h i s p a t i e n t r e c e i v e d a kidney t r a n s p l a n t . The p a t i e n t then r e c e i v e d two f u r t h e r doses o f 10 mg IV MCP as a s h o r t i n f u s i o n , over 3.5 minutes, a t 16 days p o s t - s u r g e r y and ag a i n a t 3 months a f t e r t r a n s p l a n t i o n . Informed w r i t t e n consent was o b t a i n e d on a l l o c c a s i o n s . The sampling p r o t o c o l and b i o l o g i c a l sample p r o c e s s i n g were the same as o u t l i n e d f o r t he uremic v o l u n t e e r s r e c e i v i n g the dose 24 hours p r i o r t o d i a l y s i s . In a d d i t i o n , u r i n e was c o l l e c t e d f o r 24 hours as d e s c r i b e d f o r the normal, h e a l t h y v o l u n t e e r s (see S e c t i o n 2.7.1). Labo r a t o r y i n d i c e s were reco r d e d from the p a t i e n t s * c h a r t . 2.7.6 Q u a n t i t a t i v e A n a l y s i s i n Kidney T r a n s p l a n t R e c i p i e n t Plasma, 0.1 - 0.3 mL, o r 10 uL o f u r i n e were e x t r a c t e d and d e r i v a t i z e d as o u t l i n e d i n S e c t i o n s 2.4.1 and 2.4.2. M a p r o t a l i n e (0.4 ug/mL) was used as t h e i n t e r n a l s t a n d a r d throughout the study. Each sample was measured i n d u p l i c a t e u s i n g two i n j e c t i o n s o f 2 uL each i n t o t he GC-ECD. Q u a n t i t a t i v e d e t e r m i n a t i o n o f MCP was made by f i t t i n g the area r a t i o o f the HFB d e r i v a t i v e of MCP/MAP t o the standard curve r e g r e s s i o n l i n e (area r a t i o MCP/MAP vs MCP c o n c e n t r a t i o n ) . Standard curve samples were e x t r a c t e d , d e r i v a t i z e d , and chromatographed on the same day as the v o l u n t e e r samples. 2.8 Data A n a l y s i s 2.8.1 Computer F i t t i n g F o l l o w i n g a n a l y s i s o f the b i o l o g i c a l samples f o r metoclopramide content, t he data were p l o t t e d manually t o o b t a i n i n i t i a l k i n e t i c parameter e s t i m a t e s . The c o n c e n t r a t i o n vs time data were then run by t h e d e c i s i o n making program AUTOAN (Sedman and Wagner, 1976) t o g i v e computer generated e s t i m a t e s of the k i n e t i c parameters and model. These es t i m a t e s were then independently confirmed by u s i n g the i t e r a t i v e program JANA (Dunne, 1985) t o a l s o f i t the data. The i n i t i a l e s t i m a t e s were then used by the computer program NONLIN ( M e t z l e r e t a l . , 1974) t o y i e l d f i n a l e s t i m a t e s of the k i n e t i c parameters which were used i n f u r t h e r c a l c u l a t i o n s . 2.8.2 Pharmacokinetic C a l c u l a t i o n s Area under the plasma c o n c e n t r a t i o n vs time curve was determined by the t r a p e z o i d a l approximation. The p h a r m a c o k i n e t i c v a l u e s of c l e a r a n c e , volume of d i s t r i b u t i o n , and b i o a v a i l a b i l i t y are based on s t a n d a r d c a l c u l a t i o n s g i v e n by G i b a l d i and P e r r i e r (1982). The d i a l y s i s parameters, e x t r a c t i o n e f f i c i e n c y and d i a l y z e r c l e a r a n c e , were c a l c u l a t e d by the A-V d i f f e r e n c e method d e s c r i b e d by Lee and Marbury (1984) u s i n g the formula: C a - C v A U C a " A U C v E x t r a c t i o n e f f i c i e n c y = E = — = C AUC a a where: C = plasma MCP c o n c e n t r a t i o n e n t e r i n g d i a l y s e r a C = plasma MCP c o n c e n t r a t i o n e x i t i n g d i a l y s e r AUC & = area under the plasma c o n c e n t r a t i o n vs time curve e n t e r i n g the d i a l y s e r AUC v = area under the plasma c o n c e n t r a t i o n vs time curve e x i t i n g the d i a l y s e r D i a l y s e r C l e a r a n c e = C l d = Q (1-Hct) E where: Q = bl o o d flow through the d i a l y s e r Hct = p a t i e n t s 1 h e m a t o c r i t E = e x t r a c t i o n e f f i c i e n c y T h i s method assumes t h a t the b l o o d t o plasma r a t i o of metoclopramide i s approximately 1. T h i s has been r e p o r t e d by Ross-Lee e t a l . (1981) i n human b l o o d . 2.8.3 S t a t i s t i c a l T e s t s S t a t i s t i c a l e v a l u a t i o n s were performed u s i n g e i t h e r a two-sample t - t e s t , p a i r e d t - t e s t , or one-way ANOVA t o compare mean v a l u e s between groups. A s i g n i f i c a n c e l e v e l o f p < 0.05 t w o - t a i l e d was used. 3. RESULTS 3.1 A p p l i c a b i l i t y o f assay t o uremic serum 3.1.1 E x t r a c t i o n o f blank plasma S i n c e many of the components of uremic plasma have been shown t o i n t e r f e r e w i t h t h e d e t e r m i n a t i o n of many drugs, a l i q u o t s (150, 250, 500 uL) of uremic plasma were e x t r a c t e d u s i n g the method of Riggs e t a l . (1983), t o determine p o t e n t i a l i n t e r f e r e n c e s w i t h MCP o r MAP. The r e t e n t i o n times f o r MCP and MAP are -9.3 and -11.8 minutes, r e s p e c t i v e l y . As can be seen i n F i g u r e 3, t h e r e are no i n t e r f e r i n g peaks e l u t i n g c l o s e t o the r e t e n t i o n times of MCP and MAP. O v e r a l l the chromatograms of t h e e x t r a c t e d uremic plasma appear t o be somewhat l e s s complex than comparable chromatograms from normal, h e a l t h y v o l u n t e e r s . 3.1.2 Standard curve F i g u r e 4 shows a r e p r e s e n t a t i v e s t a n d a r d curve e x t r a c t e d from uremic plasma. The s l o p e and area r a t i o s o f the p o i n t s agree q u i t e c l o s e l y w i t h those observed from normal h e a l t h y v o l u n t e e r s . Comparison w i t h r e s u l t s o b t a i n e d by Riggs e t a l . (1983) a l s o demonstrates good c o r r e l a t i o n . S i n c e no s i g n i f i c a n t d i f f e r e n c e s were noted between the standar d curve from uremic plasma and normal 1 min. Figure 3: Representative chromatograms of blank uremic plasma, extracted as per Riggs et al (1983). 1. 500 uL uremic plasma. 2. 250 uL uremic plasma. 3. 150 uL uremic plasma. HCP elutes at approximately 9.3 minutes. MAP elutes at approximately 11.8 minutes. F i g u r e 4: Standard Curve plasma, normal plasma was used i n the subsequent p r e p a r a t i o n of standard curves simultaneous t o the e x t r a c t i o n o f the p a t i e n t samples. The minimum 2 a c c e p t a b l e c o r r e l a t i o n c o e f f i c i e n t (r ) was 0.995 and the maximum a c c e p t a b l e y - i n t e r c e p t was -10% o f the h i g h e s t area r a t i o . The maximum c o e f f i c i e n t o f v a r i a t i o n of any p o i n t on the s t a n d a r d curve was 10 %. 3.2 Normal pharmacokinetics 3.2.1 Plasma K i n e t i c s The b i o a v a i l a b i l i t y and pharmacokinetics of MCP were s t u d i e d on a four-way c r o s s o v e r b a s i s i n s i x normal h e a l t h y v o l u n t e e r s . The mean k i n e t i c parameters from the plasma data are g i v e n i n T a b l e 3. The mean v a l u e of the t e r m i n a l e l i m i n a t i o n r a t e c o n s t a n t i s 0.13 0 + 0.060 h 1 . The l a r g e r v a l u e s f o r o r a l c l e a r a n c e , as compared w i t h the t o t a l body c l e a r a n c e f o l l o w i n g IV d o s i n g , suggests t h a t MCP undergoes f i r s t - p a s s metabolism. T o t a l body c l e a r a n c e when c a l c u l a t e d from e i t h e r o r a l o r IV d o s i n g i s 28.70 + 6.46 L/h. The volume of d i s t r i b u t i o n , c a l c u l a t e d v i a the area method, i s 270.26 + 127.70 L. There are no s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e s , as determined by one-way ANOVA, between the dose groups f o r t e r m i n a l e l i m i n a t i o n r a t e c o n s t a n t , b i o a v a i l a b i l i t y , t o t a l body c l e a r a n c e , or volume o f d i s t r i b u t i o n . TABLE 2 Metoclopramide k i n e t i c parameters obtained from plasma of healthy-volunteers DOSE: 5mg S o l . 10mg s o l . 10mg Tab 20mg S o l . 10mg IV Parameters: Mean±SD n 6 3 3 6 6 Ka ( h _ 1 ) 3.21±1.68 3.28± 2.71 2.78± 0.51 3.64 ±1.93 3 .29± 1.71 a (h-i) 0.6 ±0.3 0.2 0.7 0.8± 0.3 7.3 ± 5.3 * 0.12± 0.07 0.13± 0.06 0.12± 0.04 0.12 ±0.05 0.15±0.08 0.13± 0.06 AUC (ug.h/L) 155.7±111 427.9± 226 255.2 ± 41 608.0 ± 383 362.1± 66 CLi n t (L/h) 28.7 ±7.0 31.3± 9.2 25.9 ±1.2 28.8 ±7.0 28.7 ± 7.0 28.7± 6.5 Vd ( L ? r e a 273.2 ±115 318.5 ±166 235.5 ±67 287.9 ±133 242.9 ±128 270.3 ±128 F (%) 83 ± 54 124 ±38 66 ±10 84 ± 44 83 ±47 * Determined f o r those volunteers whose data f i t a two-compartment model (n= 3, 1, 1, 3, 6) 500-^ ^ F i g u r e 5: Mean Area under the Plasma C o n c e n t r a t i o n vs Time Curve (+ 1 s.d.) f o r the Normal, Healthy V o l u n t e e r s . Figure 6: Representative Plasma Concentration vs Time P r o f i l e s f o r a S i n g l e Healthy Volunteer. 5 mg Oral S o l u t i o n (o—o), 10 mg O r a l S o l u t i o n (CH-O) , 10 mg IV Bolus (•—•) , 20 mg Oral S o l u t i o n (•—•) . Although the a b s o r p t i o n r a t e c o n s t a n t , Ka, and the two-compartment d i s t r i b u t i o n a l r a t e c o n s t a n t , a l p h a , have been c a l c u l a t e d and t a b u l a t e d , t h e i r v a l u e s appear t o be q u i t e v a r i a b l e among the v o l u n t e e r s . Due t o the l a r g e p o t e n t i a l e r r o r s i n t h e i r e s t i m a t i o n no s t a t i s t i c a l t e s t s have been performed on them. AUC appears t o i n c r e a s e l i n e a r l y w i t h dose as i s shown i n F i g u r e 5. A r e p r e s e n t a t i v e s e t of plasma c o n c e n t r a t i o n vs time curves i s shown i n F i g u r e 6 f o r a normal v o l u n t e e r who r e c e i v e d 5 mg MCP o r a l s o l u t i o n , 20 mg MCP o r a l s o l u t i o n , 10 mg IV MCP, and 10 mg MCP o r a l s o l u t i o n . In t h i s f i g u r e , and i n a l l v o l u n t e e r s , the time t o peak and s l o p e o f the d e c l i n e phase appear c o n s t a n t and the plasma c o n c e n t r a t i o n s and AUC's appear t o i n c r e a s e p r o p o r t i o n a t e l y w i t h dose. The plasma data gathered from most v o l u n t e e r s f i t a two-compartment open model w i t h i n s i g n i f i c a n t l a g time f o l l o w i n g the o r a l doses. 3.2.2 U r i n a r y E x c r e t i o n For the normal v o l u n t e e r s a complete u r i n e c o l l e c t i o n was made f o r 72 hours f o l l o w i n g d o s i n g . The data was then a n a l y s e d u s i n g the amount remaining t o be e x c r e t e d (ARE) methods. F i g u r e 7 shows a r e p r e s e n t a t i v e s e t of ARE p l o t s f o r a normal h e a l t h y v o l u n t e e r . L i n e a r r e g r e s s i o n g e n e r a l l y F i g u r e 7: R e p r e s e n t a t i v e Amount Remaining t o be E x c r e t e d i n the U r i n e f o r a S i n g l e , Healthy V o l u n t e e r . 5 mg O r a l S o l u t i o n (o—o), 10 mg O r a l S o l u t i o n (•—•) , 10 mg IV Bolus (•—•) , 20 mg O r a l S o l u t i o n (•—•) . r e s u l t e d i n a c o r r e l a t i o n c o e f f i c i e n t o f > 0.95. Mean k i n e t i c parameters from the u r i n e data are r e p o r t e d i n T a b l e 4. One-way ANOVA shows no s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e s a c r o s s the dose groups. Two-sample t - t e s t i n g shows no s i g n i f i c a n t d i f f e r e n c e s , f o r comparable parameters determined from e i t h e r u r i n e o r plasma data. T h e r e f o r e , the b e s t o v e r a l l e s t i m a t e s o f these parameters are the o v e r a l l means which are r e p o r t e d i n T a b l e 5. The average p e r c e n t o f dose e x c r e t e d i n t a c t was 20.4 + 9.3 %. The t e r m i n a l e l i m i n a t i o n r a t e c o n s t a n t was 0.14 + 0.04 -1 . . . . h and the b i o a v a i l a b i l i t y was 0.68 + 0.26. Renal c l e a r a n c e (7.6 + 5.3 L/h) accounts f o r approximately 25 % of t o t a l body c l e a r a n c e . 3.3 Uremic Pharmacokinetics The c l i n i c a l h e m a t o l o g i c a l and b i o c h e m i c a l r e s u l t s , taken from the medi c a l r e c o r d s o f the uremic v o l u n t e e r s are d i s p l a y e d i n T a b l e 6. The d e t a i l s p e r t a i n i n g t o the d i a l y s i s o f the uremic p a t i e n t s are pr e s e n t e d i n T a b l e 7. 3.3.1 24 h P r e - d i a l y s i s Dose The pharmacokinetic parameters o b t a i n e d from a 10 mg IV dose of MCP i n the uremic v o l u n t e e r s are pr e s e n t e d i n T a b l e 9. A t y p i c a l plasma c o n c e n t r a t i o n v s time curve i s shown i n F i g u r e 8. The k i n e t i c parameters show a much TABLE 3 Metoclopramide pharmacokinetic parameters obtained from u r i n e data of healthy volunteers DOSE: 5 mg S o l . 10 mg s o l . 10 mg Tab. 20 mg S o l . 10 mg IV Mean+SD n 6 3 3 6 6 % dose excreted i n t a c t 16.4 ± 5.5 20.6 ±0.4 11.7 ± 0 . 2 19.5 ± 4 . 7 2 9 . 7 ± 12.3 20.4 ± 9 . 3 j 3(h-i) 0.15±0.04 0.14 ± 0 . 0 5 0.13 0.15 ±0.04 0.12 ± 0.04 0.14±0.04 CLr (L/h) 8.8 ± 9 . 4 5.7 ± 2 . 4 4.2 ± 0 . 2 7.4 ± 2 . 1 8 . 7 ± 4 . 1 7.6 ±5.3 F (%) 62 ± 2 4 56 ± 12 81 ± 25 76 ± 34 68 ± 2 6 CT> CAJ TABLE 4 Metoclopramide k i n e t i c parameters from the cumulated u r i n e and plasma r e s u l t s the normal, healthy volunteers DOSE: 5 mg S o l . 10 mg s o l . 10 mg Tab. 20 mg S o l . 10 mg IV Parameters: Mean+SD n 6 3 3 6 6 (3(h~l) 0.14±0.06 0.14 ±0.06 0.13± 0.04 0.14 ±0.05 0.14 ±0.06 0.14 ±0.05 F (%) 73±42 90±45 74 ±30 80 ±18 76+38 TABLE 5 C l i n i c a l d e t a i l s of uremic p a t i e n t s PATIENT: PB WL BM GM JS SS JT RT AGE (yr) 34 24 20 41 33 37 33 68 WEIGHT (kg) 50. 2 50 77.3 84.5 68.7 40.3 65.2 75 * Scr (mg/dL) 11. 0 17.2 13.6 15.1 16.1 11.5 17.4 15. 1 BUN* (mg/dL) 83 73 106 108 89 82 82 69 Al k Phos (I.U.) - - 38 51 128» 145 1 250» 79 Hematocrit (%) 34. 2 19.2 14.0 15.5 13.0 20.6 23.6 31. 0 Hemoglobin (g/dL) 11. 5 7.2 5.4 7.2 4.5 6.7 7.8 10. 3 * P r e - d i a l y s i s values * Serum c r e a t i n i n e and blood urea n i t r o g e n c o n c e n t r a t i o n s . * P a t i e n t s are hyperparathyroid. CTl TABLE 6 D e t a i l s p e r t a i n i n g t o the d i a l y s i s of uremic p a t i e n t s . PATIENT DIALYSER FILTER DURATION OF BLOOD FLOW TYPE DIALYSIS (h) RATE (mL/min) PB CF 1200 4.5 200 WL CF 1211 4.0 200 BM CF 1211 5.1 200 GM CF 1200 4.0 200 JS CF 1211 4.5 200 SS CF 1211 3.5 200 JT CF 1211 4.5 200 RT CF 1211 4.0 200 The CF 1200 and CF 1211 d i a l y s e r f i l t e r s are both hollow f i b r e c a p i l l a r y flow cuprophane membranes models (Travenol L a b o r a t o r i e s , D e e r f i e l d , I L L ) . The e f f e c t i v e surface area of the CF 1200 i s -1.3 sq. m while that of the CF 1211 i s - 0.9 sq. m. TABLE 7 Metoclopramide pharmacokinetic parameters from uremic volunteers 24 h p r i o r t o d i a l y s i s . PATIENT alpha i8 AUC CLtb Vd area VC E CLd (h-l) ( h - D (ug.h/L) (L/h.kg) (L/kg) (L/kg) (%) (L/h) PB 3.11 0.045 1370.7 0.14 3.11 2.93 2.0 0.10 WL 0.97 0.032 1682.4 0.12 3.71 2.02 17.0 1.00 BM 3.50 0.12 713.8 0.18 1.52 1.09 30.0 3.10 GM 7.94 0.058 471.5 0.25 4.33 1.06 5.0 0.50 JS 3.16 0.028 999.7 0.15 5.15 2.78 7.5 0.78 SS 14.39 0.015 4016.3 0.06 4.13 0.48 5.3 0.50 JT 15.66 0.099 784.7 0.19 1.94 0.16 35.0 2.80 RT 9.55 0.065 725.5 0.18 2.83 0.70 22.0 1.00 MEAN 7.29 0.058 1345.6 0.16 3.34 1.40 15.5 1.22 S.D. 5.53 0.04 1148.2 0.06 1.23 1.05 12.5 1.11 E i s the e x t r a c t i o n e f f i c i e n c y of the d i a l y s e r and CLd i s the clearance by d i a l y s i s . l a r g e r degree of i n t e r i n d i v i d u a l v a r i a b i l i t y than do the r e s u l t s o f the normal, h e a l t h y v o l u n t e e r s . 3.3.2 1 h P r e - d i a l y s i s Dose The r e s u l t s from the 10 mg IV MCP dose a d m i n i s t e r e d 1 h p r i o r t o the s t a r t of h e m o d i a l y s i s are p r e s e n t e d i n T a b l e 10. A t y p i c a l plasma c o n c e n t r a t i o n vs time p r o f i l e i s shown i n F i g u r e 10. These r e s u l t s , although i n some i n d i v i d u a l cases d i f f e r e n t , do not show s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e from the r e s u l t s d i s p l a y e d i n T a b l e 9, as determined by p a i r e d t - t e s t i n g . Again, the apparent decreases i n t o t a l body c l e a r a n c e and t e r m i n a l e l i m i n a t i o n r a t e c o n s t a n t can be seen. Furthermore, h e m o d i a l y s i s i s i n e f f e c t i v e a t c l e a r i n g MCP from the body. These r e s u l t s suggest t h a t h e m o d i a l y s i s has l i t t l e o r no e f f e c t s on.MCP k i n e t i c s . 3.4 Pharmacokinetics i n Kidney T r a n s p l a n t R e c i p i e n t The r e l e v e n t c l i n i c a l parameters f o r the kidney t r a n s p l a n t r e c i p i e n t are p r e s e n t e d i n T a b l e 11. 3.4.1 Plasma K i n e t i c s The k i n e t i c paramters o b t a i n e d are d i s p l a y e d i n T a b l e 12 and the plasma c o n c e n t r a t i o n vs time p r o f i l e s a r e p r e s e n t e d i n F i g u r e 11. P r i o r t o t h e kidney M I I I I I 0 5 10 15 20 25 30 Time,(h) F i g u r e 8: R e p r e s e n t a t i v e Plasma C o n c e n t r a t i o n vs Time P r o f i l e f o r a 10 mg IV Bolus Dose Given t o a Uremic V o l u n t e e r 24 h P r i o r t o Hem o d i a l y s i s . P r i o r t o D i a l y s i s (•—•) , D i a l y s i s ; a r t e r i a l c o n c e n t r a t i o n (•—•) , venous c o n c e n t r a t i o n (D—•) . TABLE 8 Metoclopramide pharmacokinetic parameters from uremic vo l u n t e e r s l h p r i o r to d i a l y s i s . KINETIC PARAMETER: alpha (h-1) P (h-1) AUC (ug.h/L) CLtb (L/h.kg) Vd area (L/kg) Vc (L/kg) E (%) CLd (L/h) PB 9.00 0.160 488.9 0.41 2.55 1.79 16.0 1.70 WL 0.76 0.040 1572.0 0.13 3.18 2.60 17.0 1.00 GM 2.25 0.113 349.9 0.34 2.99 2.53 22.0 2.20 JS 2.84 0.064 303.1 0.48 7.51 1.55 17.0 1.77 SS 10.50 0.012 3182.5 0.08 6.50 1.52 19.0 1.80 JT 16.41 0.102 313.3 0.48 4.71 0.13 38.0 3.40 RT 0.93 0.052 772.1 0.19 3.65 1.33 12.0 1.00 MEAN 6.10 0.078 997.4 0.30 4.44 1.64 20.1 1.84 S.D. 5.98 0.050 1063.3 0.17 1.9 0.83 8.4 0.8 # P a t i e n t BM received a kidney a l l o g r a f t p r i o r t o the second a d m i n i s t r a t i o n of metoclopramide. E i s the e x t r a c t i o n e f f i c i e n c y of the d i a l y s e r ; CLd i s the clearance by d i a l y s i s . IOCH H • 1 i 1 1 1 n O 5 10 1 5 2 0 2 5 3 0 Time^h) F i g u r e 9: R e p r e s e n t a t i v e Plasma C o n c e n t r a t i o n vs Time P r o f i l e f o r a 10 mg IV Bolus Dose Given t o a Uremic Vo l u n t e e r 1 h P r i o r t o Hemodialysis. P r i o r t o D i a l y s i s (•—•) , D i a l y s i s ; a r t e r i a l c o n c e n t r a t i o n (•—•) , venous c o n c e n t r a t i o n (o—•) , P o s t - D i a l y s i s (o-»o) . TABLE 9 C l i n i c a l parameters f o r uremic p a t i e n t BM before and a f t e r r e n a l t r a n s p l a n t a t i o n . PARAMETER: DATE WEIGHT,(kg) BEFORE Nov. 20/83 77.3 SERUM CREATININE,(mg/dL) 13.6 BLOOD UREA NITROGEN,(mg/dL) 106 16 DAYS AFTER Sept. 10/85 73.5 1.8 35 3 MONTHS AFTER Dec. 6/85 84.5 1.7 29 F i g u r e 10: Plasma C o n c e n t r a t i o n vs Time p r o f i l e s f o r the Kidney T r a n s p l a n t R e c i p i e n t F o l l o w i n g 10 mg IV Bolus Dose. Uremia (•—•) , 15 days A f t e r T r a n s p l a n t (o—o) , 3 months A f t e r T r a n s p l a n t (•—•) . oo t r a n s p l a n t the k i n e t i c paramters show a p a t t e r n t y p i c a l o f t h e uremic v o l u n t e e r s , v i z . . extended h a l f - l i f e and d e creased t o t a l body c l e a r a n c e . However, f o l l o w i n g t r a n s p l a n t a t i o n the k i n e t i c parameters are d r a m a t i c a l l y a l t e r e d , as evidenced by F i g u r e 11, and f a l l w i t h i n the range d i s p l a y e d by the normal h e a l t h y v o l u n t e e r s . 3.4.2 U r i n a r y E x c r e t i o n The e x c r e t i o n of MCP i n the u r i n e a p p a r e n t l y reaches normal l e v e l s , although i n the lower range seen i n normals, f o l l o w i n g t r a n s p l a n t a t i o n as evidenced by the p e r c e n t o f dose e x c r e t e d i n t a c t and the r e n a l c l e a r a n c e v a l u e s of MCP. These r e s u l t s are p r e s e n t e d i n T a b l e 13. TABLE 10 Metoclopramide pharmacokinetic parameters f o r uremic v o l u n t e e r BM be f o r e and a f t e r kidney t r a n s p l a n t a t i o n . PARAMETER BEFORE 16 DAYS AFTER 3 MONTHS AFTER a^h" 1) 6.08 8.70 6.19 |3, (h-i) 0.11 0.21 0.21 AUC,(ug.h/L) 713.8 316.9 145.9 Vdarea,(L/kg) 1.52 2.10 3.74 CLtb,(L /h/kg) 0.18 0.43 0.81 CLr,(L / h .kg) 0.06 0.08 CLnr,(L /h/kg) 0.18 0.37 0.73 % dose exc r -eted i n t a c t 0 14 10 CLtb, i s t o t a l body c l e a r a n c e ; and C l n r , i s nonrenal drug c l e a r a n c e . TABLE 11 Metoclopramide Pharmacokinetic parameters from the u r i n e o f t h e kidney t r a n s p l a n t r e c i p i e n t PARAMETER BEFORE 16 DAYS AFTER 3 MONTHS AFTER CLr,(L/h.kg) 0.06 0.08 % dose e x c r -eted i n t a c t 0 14 10 4. DISCUSSION 4.1 A p p l i c a b i l i t y o f Assay t o Uremic Plasma A n a l y s i s o f drugs i n b i o l o g i c a l samples from p a t i e n t s can o f t e n p r e s e n t d i f f i c u l t i e s i n both q u a n t i t a t i o n and i n t e r p r e t a t i o n s i n c e the p a t i e n t samples may c o n t a i n substances not encountered i n samples from normal, h e a l t h y v o l u n t e e r s (Perucca e t a l . , 1985). T h i s may be o f p a r t i c u l a r s i g n i f i c a n c e i n uremic p a t i e n t s whose plasma w i l l c o n t a i n many substances n o r m a l l y e x c r e t e d o r c a t a b o l i z e d by the kidney. The a b i l i t y t o overcome th e s e p o t e n t i a l problems i s a f u n c t i o n o f both the assay s e l e c t i v i t y and the s e l e c t i v i t y o f t h e d e t e c t i o n mode. For i n s t a n c e , the use o f flame i o n i z a t i o n d e t e c t i o n (FID) i s o f t e n d i f f i c u l t and l i m i t e d i n t he a n a l y s i s o f uremic plasma s i n c e many low weight, v o l a t i l e compounds are c a r r i e d over d u r i n g sample e x t r a c t i o n and can i n t e r f e r e w i t h drug d e t e c t i o n and q u a n t i t a t i o n . The chromatograms ( F i g . 3) and st a n d a r d curve ( F i g . 4) demonstrate the a b i l i t y o f t h i s assay (Riggs e t a l . . 1983) procedure t o d e t e c t and q u a n t i f y MCP i n a s e l e c t i v e , and l i n e a r manner from uremic p a t i e n t plasma samples. The l a c k o f i n t e r f e r e n c e o f the c o n t e n t s o f the uremic plasma l i k e l y stems from the use o f a double e x t r a c t i o n procedure which removes almost a l l p o t e n t i a l l y i n t e r f e r i n g compounds, and/or the r e l a t i v e s e l e c t i v i t y of the e l e c t r o n capture d e t e c t o r (ECD). S i n c e none o f the b l a n k chromatograms showed i n t e r f e r e n c e , the volume o f plasma chosen t o be e x t r a c t e d f o r most o f the uremic plasma samples was 200 uL. T h i s allowed area r a t i o s t o be o b t a i n e d t h a t were approximately i n the middle of the s t a n d a r d curve and r e s e r v e d enough plasma t o a l l o w the assay t o be performed once more i n case of problems w i t h one o r both d u p l i c a t e s . I f the area r a t i o f e l l o u t s i d e t h e range of the s t a n d a r d curve, another a l i q u o t as e x t r a c t e d , u s i n g a more a p p r o p r i a t e volume, t o p r o v i d e an a c c u r a t e q u a n t i t a t i o n of drug. In g e n e r a l , however, t h e r e was i n s u f f i c i e n t plasma t o measure more than two s e t s of d u p l i c a t e s f o r any s i n g l e sample. In summary, the assay method was found t o be adequate t o a c c u r a t e l y d e t e c t and q u a n t i f y t r a c e l e v e l s of MCP i n uremic plasma over the e n t i r e experimental time p e r i o d . 4.2 Normal Pharmacokinetics The c r o s s o v e r study i n the normal h e a l t h y v o l u n t e e r s was designed t o answer two major q u e s t i o n s r e g a r d i n g MCP p h a r m a c o k i n e t i c s : 1) Does MCP d i s p l a y l i n e a r p harmacokinetics over the dose range of 5 - 20 mg i n s p i t e of the p r e v i o u s l i t e r a t u r e c l a i m s of dose-dependency ? 2) Given the experimental l i m i t a t i o n s of the e x i s t i n g l i t e r a t u r e what are the a b s o l u t e and r e l a t i v e b i o a v a i l a b i l i t i e s of MCP ? The accumulated data p r o v i d e enough i n f o r m a t i o n t o d e f i n i t i v e l y answer these q u e s t i o n s and t o shed some doubt o f the i n t e r p r e t a t i o n s of p r e v i o u s a u t h o r s . Both the u r i n e and plasma r e s u l t s p o i n t t o the e x i s t e n c e o f l i n e a r p harmacokinetics over the dose range examined. In T a b l e 2 t h i s i s demonstrated by s e v e r a l p o i n t s : 1) The c o n s t a n t v a l u e s of beta f o r each dose l e v e l . 2) The c o n s t a n t v a l u e of t o t a l body c l e a r a n c e . 3) The c o n s t a n t v a l u e of volume of d i s t r i b u t i o n . 4) The c o n s t a n t v a l u e of b i o a v a i l a b i l i t y . 5) The p r o p o r t i o n a l i n c r e a s e i n AUC w i t h dose (see a l s o F i g . 5 ) . The plasma c o n c e n t r a t i o n vs time curve ( F i g . 6 ) a l s o i l l u s t r a t e s the presence o f l i n e a r k i n e t i c s . T h i s can be seen by the p a r a l l e l nature o f the t e r m i n a l s l o p e s , the s i m i l a r time t o peak plasma c o n c e n t r a t i o n f o l l o w i n g o r a l d o s i n g , and the p r o p o r t i o n a t e i n c r e a s e s i n both plasma c o n c e n t r a t i o n and AUC w i t h dose. The u r i n e data a l s o c o n f i r m s , independently, the e x i s t e n c e o f l i n e a r k i n e t i c s . F i g u r e 7 shows a p a r a l l e l d e c l i n e i n the amount remaining t o be e x c r e t e d (ARE) vs time p l o t s s u g g e s t i n g e q u i v a l e n t e l i m i n a t i o n h a l f - l i v e s . F u r t h e r t h e r e i s a p r o p o r t i o n a l i n c r e a s e i n the t o t a l amount e x c r e t e d unchanged w i t h dose. Ta b l e 4 a l s o shows t h i s through the c o n s t a n t v a l u e s of beta, r e n a l c l e a r a n c e , b i o a v a i l a b i l i t y , and percentage e x c r e t e d i n t a c t . In a d d i t i o n t h e r e i s no s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e between the k i n e t i c parameter v a l u e s o b t a i n e d from plasma and u r i n e . Thus i t i s demonstrated t h a t MCP undergoes l i n e a r pharmacokinetics w i t h i n the dose range from 5 - 2 0 mg. The p r e v i o u s f i n d i n g i s i n d i r e c t c o n t r a s t t o p r e v i o u s l y p u b l i s h e d and w i d e l y accepted r e s u l t s . However, the data and i n t e r p r e t a t i o n s t h a t have l e d t o the p r e v i o u s c l a i m s of dose-dependency deserve c l o s e s c r u t i n y . The two major c l a i m s f o r dose-dependency of MCP k i n e t i c s have been made by G r a f f n e r e t a l . (1979) and by Bateman e t a l . (1980). G r a f f n e r e t a l . (1979) a d m i n i s t e r e d IV doses of 5 and 10 mg, and o r a l s o l u t i o n and s l o w - r e l e a s e t a b l e t of 20 mg t o f i v e male v o l u n t e e r s . Based on observed, but s t a t i s t i c a l l y unproven, o b s e r v a t i o n s of d i f f e r e n c e s i n beta h a l f - l i f e (4.4 + 1.2 h f o r the 5 mg IV dose vs 5.4 + 1.8 h f o r the 10 mg IV dose) the s e workers concluded t h a t the e l i m i n a t i o n h a l f - l i f e o f MCP was dose-dependent. A d d i t i o n a l l y , they c i t e d an observed d i f f e r e n c e i n the percentage e x c r e t e d unchanged i n the u r i n e ( 16 + 4 % f o r the 5 mg IV dose vs 21 + 7 % f o r the 10 mg IV dose) and an average i n c r e a s e o f 150% i n the AUC on d o u b l i n g the dose as evidence o f n o n - l i n e a r k i n e t i c s . There are s e v e r a l problems w i t h the i n t e r p r e t a t i o n s o f these r e s u l t s made by thes e a u t h o r s . F i r s t l y , t he l a c k o f s t a t i s t i c a l demonstration o f d i f f e r e n c e s i n the mean v a l u e s i s i n a p p r o p r i a t e . A p p r o p r i a t e t e s t i n g would have demonstrated no s i g n i f i c a n t d i f f e r e n c e s i n these v a l u e s . Secondly, the HPLC-UV d e t e c t i o n assay used, p r o v i d e d s u f f i c i e n t s e n s i t i v i t y t o measure MCP i n plasma f o r o n l y 8 h a f t e r drug a d m i n i s t r a t i o n . The t r u n c a t i o n o f the sampling p e r i o d can l e a d t o u n d e r e s t i m a t i o n o f the b i o l o g i c a l h a l f - l i f e ( G i b a l d i and Weintraub, 1971) and i n t h i s case c o u l d e x p l a i n the s h o r t e r h a l f - l i f e noted f o l l o w i n g the 5 mg IV dose. F i n a l l y , the authors mention t h a t the d o u b l i n g o f the dose p r o v i d e s an approximately p r o p o r t i o n a l i n c r e a s e i n plasma c o n c e n t r a t i o n . T h i s o b s e r v a t i o n c o n t r a s t s d i r e c t l y w i t h the c l a i m o f dose-dependent k i n e t i c s . The second study c l a i m i n g dose-dependency of MCP k i n e t i c s (Bateman e t a l . . 1980) i s a l s o s i m i l a r l y flawed. MCP was g i v e n as 10 mg IV and 10 and 20 mg as o r a l t a b l e t s . Based on s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e s i n e l i m i n a t i o n h a l f - l i f e , p a r t i c u l a r l y f o l l o w i n g the o r a l doses, the authors c l a i m t h a t t h e r e a re dose-dependent changes i n MCP e l i m i n a t i o n h a l f - l i f e . While the d i f f e r e n c e s do appear t o be s t a t i s t i c a l l y s i g n i f i c a n t , t he e n t i r e sampling d u r a t i o n was o n l y 6 hours which c o u l d l e a d t o s i g n i f i c a n t i n a c c u r a c y i n the est i m a t e d h a l f - l i f e p a r t i c u l a r l y a t the lower dose l e v e l . The range of b i o a v a i l a b i l i t y observed i n t h i s study was from 32 - 97 % s u g g e s t i n g the e x i s t e n c e of f i r s t - p a s s metabolism f o l l o w i n g o r a l d o s i n g . T h i s i m p l i e s t h a t the a c t u a l amounts of drug r e a c h i n g the syste m i c c i r c u l a t i o n f o l l o w i n g o r a l a d m i n i s t r a t i o n o f 10 and 2 0 mg are, a t l e a s t 3.2 - 6.4 mg and, a t most, 9.7 -19.4 mg. The e l i m i n a t i o n h a l f - l i f e e s t i m a t e d f o r the 10 mg IV dose, however, i s l e s s than t h a t o f e i t h e r t he 10 or 2 0 mg o r a l dose. I f dose-dependent k i n e t i c s d i d i n f a c t e x i s t and a s i g n i f i c a n t f i r s t - p a s s e f f e c t d i d e x i s t , then the h a l f - l i f e f o l l o w i n g IV a d m i n i s t r a t i o n would be the l a r g e s t s i n c e the IV rou t e would p r o v i d e the l a r g e s t amount o f drug t o the body. In a subsequent review o f the l i t e r a t u r e on MCP k i n e t i c s Bateman (198 3), compares r e s u l t s from s e v e r a l pharmacokinetic s t u d i e s , without b e n e f i t o f s t a t i s t i c a l t e s t s , t o demonstrate t h a t MCP does not obey l i n e a r k i n e t i c s . T h i s review f a i l s t o c r i t i c a l l y e v a l u a t e the e a r l y l i t e r a t u r e and f a i l s t o e x p l a i n some o b s e r v a t i o n s o f the k i n e t i c s o f 'high-dose" MCP used i n cancer chemotherapy. R e s u l t s from ph a r m a c o k i n e t i c s t u d i e s i n cancer chemotherapy employing doses i n excess o f 0.5 mg/kg/h ( T a y l o r e t a l . . 1984, Bryson e t a l . , 1985) have demonstrated the e x i s t e n c e o f l i n e a r MCP k i n e t i c s a t these dose l e v e l s . R e c e n t l y , Wright e t a l . (1984) have demonstrated l i n e a r k i n e t i c s a t doses between 2 0 and 100 mg. I t cannot be argued t h a t MCP a t lower doses i n humans d i s p l a y s the same type of n o n l i n e a r k i n e t i c s d i s p l a y e d i n the r a t , s i n c e the o b s e r v a t i o n s made by K a p i l e t a l . (1984) a r e q u a l i t a t i v e l y v e r y d i f f e r e n t from the c l a i m s o f the authors w i t h regards t o the human work. In a d d i t i o n , i t i s not p o s s i b l e t o e x t r a p o l a t e r e s u l t s from r a t d i r e c t l y t o humans f o r MCP s i n c e the m e t a b o l i c p a t t e r n s o f MCP d i f f e r s u b s t a n t i a l l y between the two s p e c i e s ( A r i t a and H o r i , 1970; Teng e t a l . f 1977). The q u e s t i o n o f the a b s o l u t e and r e l a t i v e b i o a v a i l a b i l i t i e s of MCP have been addressed by s e v e r a l groups (Schuppan e t a l . . 1979; G r a f f n e r e t a l . . 1979; Bateman e t a l . , 1980; Ross-Lee e t a l . f 1981; Block e t  a l . , 1981). However, as o u t l i n e d e a r l i e r , a l l o f the s e s t u d i e s s u f f e r from l i m i t a t i o n s which may reduce the c r e d i b i l i t y o f t h e i r r e s u l t s . G e n e r a l l y , t h e s e l i m i t a t i o n s are of t h r e e t y p e s . Many o f the e a r l y assay procedures had low s e n s i t i v i t y and/or poor s e l e c t i v i t y (Schuppan e t a l . . 1979; Bateman e t a l . . 1980). T h i s problem l e d t o s h o r t sampling p e r i o d s f o l l o w i n g d o s i n g which may not a l l o w a c c u r a t e e s t i m a t i o n o f many k i n e t i c parameters ( G i b a l d i and Weintraub, 1971). S e v e r a l groups used a t a b l e t o r c a p s u l e as the s o l e o r a l dosage form (Schuppan e t a l . . 1979; G r a f f n e r e t a l . . 1979; Bateman e t  a l . . 1980; Ross-Lee e t a l . , 1981). S i n c e d i s s o l u t i o n r a t e can s i g n i f i c a n t l y a f f e c t b i o a v a i l a b i l i t y , a more a p p r o p r i a t e comparison t o determine a b s o l u t e b i o a v a i l a b i l i t y would have been made w i t h an o r a l s o l u t i o n . F i n a l l y , the comparison o f unequal o r a l and IV doses (Schuppan e t a l . . 1979; G r a f f n e r e t a l . . 1979; Blo c k e t a l . . 1980) was not a p p r o p r i a t e s i n c e the d o s e - l i n e a r i t y o f MCP k i n e t i c s w i t h i n t h i s dose range had not been e s t a b l i s h e d and the e x i s t i n g evidence was, i n f a c t , q u i t e t o the c o n t r a r y . More s p e c i f i c a l l y the weaknesses o f each study are as f o l l o w s . Schuppan e t a l . (1979) used a t h i n l a y e r chromatographic method t o q u a n t i t a t e MCP. With t h i s method t h e i r minimum d e t e c t a b l e c o n c e n t r a t i o n was e n t i r e l y inadequate (40 ng/mL) and t h e i r assay o n l y a l l o w e d f o r plasma sampling and measurement f o r 10 h f o l l o w i n g drug a d m i n i s t r a t i o n . In t o t a l , o n l y 8 plasma samples were taken from each s u b j e c t , furthermore, no assessment o f drug e x c r e t i o n i n the u r i n e was made. These authors made t h e i r k i n e t i c comparisons based on unequal IV and o r a l doses without demonstration o f the e x i s t e n c e o f l i n e a r k i n e t i c s (50 mg o r a l l y v s 20 mg I V ) . A d d i t i o n a l l y , a c a p s u l e was used as the o r a l r e f e r e n c e dosage form i n s p i t e o f the f a c t t h a t o b t a i n i n g o r making an o r a l s o l u t i o n was p o s s i b l e . These authors observed an a b s o l u t e b i o a v a i l a b i l i t y o f ~50 %. G r a f f n e r e t a l . (1979) compared the b i o a v a i l a b i l i t y o f a 20 mg MCP o r a l t a b l e t w i t h the a d m i n i s t r a t i o n o f 5 and 10 mg IV. No c l e a r demonstration o f l i n e a r k i n e t i c s were made by the authors. In f a c t , these authors suggested the presence o f n o n - l i n e a r k i n e t i c s . I f t h i s were t r u e , then the assesment of b i o a v a i l a b i l i t y from unequal doses would have been i m p o s s i b l e . However, the s e workers go on t o suggest t h a t the a b s o l u t e b i o a v a i l a b i l i t y i s between 25 - 40 %. Bateman e t a l . (1980) compared the a v a i l a b i l i t y o f 10 and 2 0 mg MCP g i v e n as the o r a l t a b l e t w i t h 10 mg g i v e n IV. Due t o i n h e r e n t assay i n s e n s i t i v i t y , plasma was c o l l e c t e d f o r a maximum o f 8 h. Consequently, t h i s sampling approach l e d t o a requirement f o r e x t e n s i v e e x t r a p o l a t i o n o f the b l o o d curve t o a l l o w c a l c u l a t i o n o f the AUC from 0 t o i n f i n i t y . As w e l l , a d m i n i s t r a t i o n o f a t a b l e t dosage form b e f o r e a complete assessment was made w i t h an o r a l s o l u t i o n has l e d t o some c o n f u s i o n s i n c e t a b l e t d i s s o l u t i o n r a t e can s u b s t a n t i a l l y a l t e r t he observed b i o a v a i l a b i l i t y f o r a h i g h c l e a r a n c e drug. These authors noted s u b s t a n t i a l i n t e r - i n d i v i d u a l d i f f e r e n c e s i n b i o a v a i l a v i l i t y r a n g i n g from 32 - 97 % w i t h l i t t l e e x p l a n a t i o n f o r the observed v a r i a b i l i t y . Again, no use was made of u r i n e data. B l o c k e t a l . (1980) compared the a b s o l u t e and r e l a t i v e b i o a v a i l a b i l i t i e s of MCP i n s e v e r a l d i f f e r e n t dosage forms. T h e i r HPLC method o n l y allowed q u a n t i t a t i o n up t o 12 h f o l l o w i n g dose thus r e q u i r i n g s i g n i f i c a n t e x t r a p o l a t i o n t o o b t a i n the n e c e s s a r y AUC v a l u e s . In a d d i t i o n , the accuracy of the dose of the o r a l s o l u t i o n appears somewhat q u e s t i o n a b l e , s i n c e t h e s e authors c l a i m t h a t 30 drops was equal t o 10 mg MCP. The use of a drop i s u n s c i e n t i f i c s i n c e the volume may v a r y s u b s t a i n t i a l l y and not a l l o w a c c u r a t e knowledge of t h e a d m i n i s t e r e d dose. F u r t h e r , t h i s group d i d not compare equal o r a l and IV doses (18 mg IV vs 27 mg o r a l l y ) i n s p i t e o f the o b s e r v a t i o n s of the p o s s i b i l i t y of the e x i s t e n c e o f n o n - l i n e a r k i n e t i c s . These authors suggest a b i o a v a i l a b i l i t y of 76 - 79 % f o r o r a l MCP forms and 53 % f o r r e c t a l l y a d m i n i s t e r e d MCP. Ross-Lee e t a l . used an ECD-GC method t o q u a n t i t a t e MCP i n plasma and t o determine the a b s o l u t e b i o a v a i l a b i l i t y of a 10 mg o r a l dose vs 10 mg MCP IV. However, q u a n t i t a t i o n was o n l y p o s s i b l e f o r 10 h a f t e r drug a d m i n i s t r a t i o n ; a g a i n u r i n e data was not used as an independent c o n f i r m a t i o n of the f i n d i n g s u s i n g plasma d a t a . These authors c l a i m b i o a v a i l a b i l i t y o f 77 % (range 47 - 114 % ) . These s t u d i e s were reviewed by Bateman (1983) but no t r u e c r i t i c a l d i s s e c t i o n was made. Subsequent t o t h i s work, Wright e t a l . (1984) have demonstrated b i o e q u i v a l e n c e between 20 mg as o r a l s o l u t i o n and 20 mg as o r a l t a b l e t . No demonstration of b i o e q u i v a l e n c e has been made a t lower doses, 5 - 20 mg, which are more commonly encountered i n ambulatory p a t i e n t t h e r apy. The p r e s e n t study attempts t o overcome the p r e v i o u s l y mentioned l i m i t a t i o n s i n s e v e r a l ways. The ECD-GC method i s much more s e n s i t i v e and s p e c i f i c than the p r e v i o u s assays a l l o w i n g more a c c u r a t e q u a n t i t a t i o n over a l o n g e r sampling p e r i o d . In a d d i t i o n , t h i s study demonstrates the l i n e a r i t y o f MCP k i n e t i c s and compares equal doses of IV MCP and a r a p i d l y a v a i l a b l e o r a l s o l u t i o n dosage form. Furthermore, a comparison between the o r a l s o l u t i o n and the o r a l t a b l e t i s a l s o p o s s i b l e . The r e s u l t s of the b i o a v a i l a b i l i t y assesments are c l e a r from T a b l e s 3, 4, and 5. The b e s t e s t i m a t e of the a b s o l u t e b i o a v a i l a b i l i t y of MCP i s 78% u s i n g the cumulated data from the plasma and u r i n e . I t s h o u l d be noted, however, t h a t t h e r e i s s i g n i f i c a n t i n t e r - i n d i v i d u a l v a r i a b i l i t y . The r e l a t i v e b i o a v a i l a b i l i t y o f the t a b l e t and s o l u t i o n appears t o be -100 % s u g g e s t i n g t h a t t a b l e t d i s s o l u t i o n r a t e does not p l a y a s i g n i f i c a n t r o l e i n the a b s o r p t i v e s t e p f o r MCP. T h i s may r e s u l t from the f a c t t h a t the h e p a t i c c l e a r a n c e o f MCP i s more i n t e r m e d i a t e than t r u l y h i g h . I f t h i s i s t r u e then MCP c l e a r a n c e would o n l y be p a r t i a l l y s e n s i t i v e t o h e p a t i c b l o o d flow or the r a t e o f d e l i v e r y o f drug t o t h e l i v e r ( W i l k i n s o n and Shand, 1975). Thus, i f the d i f f e r e n c e i n d e l i v e r y of the s o l u t i o n and t a b l e t are o n l y s u b t l y d i f f e r e n t they may be i n d i s t i n g u i s h a b l e t o t h i s method of study. The r e s u l t s o b t a i n e d from the u r i n e data independently c o n f i r m those o b t a i n e d from the plasma of the normal h e a l t h y v o l u n t e e r s . T h i s may a l s o be i n f e r r e d from the f a c t t h a t the t a b l e t and s o l u t i o n s have approximately the same time t o peak and reach approximately the same plasma c o n c e n t r a t i o n s . The i n d i v i d u a l k i n e t i c parameters i n T a b l e s 3, 4, and 5 do not d i f f e r g r e a t l y from those r e p o r t e d e a r l i e r . In summary, the beta h a l f - l i f e appears t o be -5.4 h, w i t h t o t a l body c l e a r a n c e b e i n g -28.7 L/h and the volume o f d i s t r i b u t i o n b e i n g r e l a t i v e l y l a r g e a t -270.1 L. Renal e x c r e t i o n accounts f o r -21 % of the t o t a l dose. Although most o f the h e a l t h y v o l u n t e e r data ws b e s t e x p l a i n e d u s i n g a two-compartment model i n some cases the o r a l dose p r o f i l e f i t a one-compartment open model, which may r e s u l t from t h e v a l u e of a l p h a b e i n g l a r g e r than Ka ( G i b a l d i and P e r r i e r , 1982). 4.3 Uremic Pharmacokinetics From the i n f o r m a t i o n a v a i l a b l e i n both t h i s study and those t h a t have been p r e v i o u s l y completed i n normal h e a l t h y v o l u n t e e r s , t h e r e i s no apparent reason t o expect t h a t t h e pharmac o k i n e t i c s of MCP should be s u b s t a n t i a l l y a l t e r e d by kidney d i s e a s e . In normals, MCP i s o n l y about 20% e x c r e t e d unchanged i n the u r i n e . Although a l a r g e p r o p o r t i o n o f the o r a l dose of MCP.is s u l p h a t e d , a t the 4 . . . N p o s i t i o n , s u l p h a t i o n i s g e n e r a l l y b e l i e v e d t o be r e l a t i v e l y u n a f f e c t e d i n c h r o n i c r e n a l f a i l u r e (Reidenberg, 1977). In a d d i t i o n , MCP i s o n l y s l i g h t l y , - 4 0 % , p r o t e i n bound and r e n a l f a i l u r e has been shown t o have l i t t l e e f f e c t on t h i s v a l u e (Webb e t a l . . 1986). Thus, pharmacokinetic changes, which may occur i n r e n a l l y i mpaired p a t i e n t s , would not be expected t o occur f o r MCP. C l i n i c a l e x p e r i e n c e u s i n g MCP as an a n t i e m e t i c / a n t i n a u s e a n t i n p a t i e n t s w i t h decreased kidney f u n c t i o n , however, has suggested otherwise. E a r l y r e p o r t s , p u b l i s h e d i n Lancet, noted an much h i g h e r i n c i d e n c e o f adverse e f f e c t s t o MCP, p a r t i c u l a r l y those o f CNS o r i g i n , i n uremic p a t i e n t s ( C a r a l p s , 1979; Bateman and Davies, 1979). P r e l i m i n a r y i n v e s t i g a t i o n (Bateman, 1980) suggested t h a t the t o t a l body c l e a r a n c e o f MCP i n uremics was reduced approximately 3 f o l d i n uremic p a t i e n t s w i t h an attendent, p r o p o r t i o n a l i n c r e a s e i n e l i m i n a t i o n h a l f - l i f e . Three s t u d i e s , two i n humans (Bateman e t a l . . 1981; Lehmann e t a l . . 1985) and one i n r a t s (Tam e t a l . ; 1981), have examined the i n f l u e n c e o f r e n a l f a i l u r e on MCP k i n e t i c s i n more d e t a i l . Tam e t a l . (1981) used b i l a t e r a l u r e t e r a l l i g a t i o n , u r a n y l n i t r a t e a d m i n i s t r a t i o n , and 5/6 two s t e p nephrectomy t o p r o v i d e a range of e x p e r i m e n t a l l y induced r e n a l f a i l u r e i n r a t s . F o l l o w i n g a d m i n i s t r a t i o n of MCP they noted a t l e a s t a two f o l d i n c r e a s e i n AUC and e l i m i n a t i o n h a l f - l i f e i n the animals w i t h r e n a l f a i l u r e . T o t a l body c l e a r a n c e was decreased by a s i m i l a r p r o p o r t i o n . These r e s u l t s have been e s s e n t i a l l y p a r a l l e l e d i n the work of Bateman e t a l . (1981) and Lehmann e t a l . (1985) u s i n g human s u b j e c t s . However, g i v e n the i n t e r s p e c i e s d i f f e r e n c e s between r a t and man the mechanisms r e s p o n s i b l e f o r t h i s change may not be the same. Bateman e t a l . (1981) examined the k i n e t i c s of MCP f o l l o w i n g IV and o r a l a d m i n i s t r a t i o n of 10 mg MCP t o s i x p a t i e n t s w i t h v a r y i n g degrees o f r e n a l f a i l u r e , two o f whom were an e p h r i c and on h e m o d i a l y s i s . These authors noted a r e d u c t i o n of t o t a l body c l e a r a n c e t o l e v e l s approximately 30 % of those seen i n normal h e a l t h y v o l u n t e e r s w i t h an attendent, p r o p o r t i o n a l i n c r e a s e i n e l i m i n a t i o n h a l f - l i f e . Volume o f d i s t r i b u t i o n (289.6 + 18.23 L) was not s i g n i f i c a n t l y d i f f e r e n t from t h a t seen i n normal, h e a l t h y v o l u n t e e r s . No i n f o r m a t i o n was p r o v i d e d on the e x t e n t o f removal of MCP by h e m o d i a l y s i s . These r e s u l t s suggested t h a t the i n c r e a s e d i n c i d e n c e o f adverse e f f e c t s noted i n uremic p a t i e n t s g i v e n MCP c o u l d be r e l a t e d t o accumulation o f MCP due t o reduced t o t a l body c l e a r a n c e . A d d i t i o n a l l y , t h e s e authors suggest t h a t the change i n k i n e t i c s cannot be s o l e l y e x p l a i n e d by the r e d u c t i o n o f r e n a l c l e a r n a c e s i n c e t h i s o n l y accounts f o r ~20 % o f t o t a l body c l e a r a n c e . A more e x t e n s i v e study, c o v e r i n g a l a r g e range o f r e n a l impairment, i n humans has been completed by Lehmann e t a l . (1985). These authors confirmed the p r e v i o u s l y mentioned e f f e c t s o f uremia on MCP k i n e t i c s but a l s o found a p o s i t i v e c o r r e l a t i o n between t o t a l body c l e a r a n c e o f MCP and the degree o f renal.impairment, as d e f i n e d by c r e a t i n i n e c l e a r a n c e ( r = 0.78). Although removal by h e m o d i a l y s i s was examined, the authors i n t e r p r e t a t i o n o f t h i s i s somewhat confused. They s t a t e t h a t h e m o d i a l y s i s was r e s p o n s i b l e f o r an a d d i t i o n a l 60 % i n c r e a s e i n t o t a l body c l e a r a n c e y e t t h a t i t c l e a r e d r e l a t i v e l y l i t t l e o f the body l o a d o f MCP. In a d d i t i o n , the quoted h e m o d i a l y s i s c l e a r a n c e s (94.6 mL/min, 111.0 mL/min, 84.9 mL/min, and 73.4 mL/min) are extremely h i g h when compared t o t o t a l body c l e a r a n c e and i f compared w i t h e s t a b l i s h e d v a l u e s f o r many drugs. I n t e r e s t i n g l y , a case r e p o r t ( B e r a r d i e t a l . , 1986) d e s c r i b i n g MCP removal i n a s i n g l e p e r i t o n e a l d i a l y s i s p a t i e n t removed l e s s than 10 ug of MCP from the body s u g g e s t i n g t h a t p e r i t o n e a l d i a l y s i s i s an i n e f f i c i e n t method of removing MCP. These authors (Lehmann e t a l . 1985) s p e c u l a t e t h a t the reduced t o t a l body c l e a r a n c e noted i n r e n a l f a i l u r e may r e s u l t from changes i n r e n a l drug metabolism o r e n t e r o h e p a t i c r e c i r c u l a t i o n . However, no evidence i s o f f e r e d t o support t h e s e s p e c u l a t i o n s . Although the authors suggest s t r o n g l y t h a t the change may be i n r e n a l metabolism, t h i s has been shown not t o occur i n r a t s ( K a p i l e t a l . . 1984). Given the p r e v i o u s i n v e s t i g a t i o n s on MCP, t h i s study was designed t o answer two major q u e s t i o n s as w e l l as t o more f u l l y d e s c r i b e the k i n e t i c s of MCP i n p a t i e n t s w i t h severe r e n a l impairment. 1) What i s the e x t e n t of removal of MCP by h e m o d i a l y s i s ? 2) Does h e m o d i a l y s i s have any e f f e c t s on the subsequently d i s p l a y e d k i n e t i c s of MCP? Subsequently, one of the uremic p a t i e n t s (BM) r e c e i v e d a kidney t r a n s p l a n t which allowed i n v e s t i g a t i o n of the e f f e c t s of the renewed r e n a l f u n c t i o n on the d i s p l a y e d MCP k i n e t i c s . Q u a l i t a t i v e l y the k i n e t i c r e s u l t s o b t a i n e d i n t h i s study p a r a l l e l those p r e v i o u s l y r e p o r t e d . There i s a t l e a s t a t w o - f o l d decrease i n t o t a l body c l e a r a n c e w i t h a p r o p o r t i o n a t e i n c r e a s e i n e l i m i n a t i o n h a l f - l i f e and i n s i g n i f i c a n t change i n volume of d i s t r i b u t i o n . A l l the uremic p a t i e n t data was b e s t f i t by a two compartmental model. The d i s t r i b u t i o n a l r a t e c o n s t a n t , a l p h a , was v e r y much g r e a t e r than the beta r a t e c o n s t a n t . The volume of the c e n t r a l compartment was q u i t e l a r g e a c c o u n t i n g f o r an average of approximately 30 - 40 % o f the t o t a l volume of d i s t r i b u t i o n . The most s t r i k i n g f e a t u r e of the uremic k i n e t i c data i s the degree of i n t e r - i n d i v i d u a l v a r i a t i o n . T h i s l a r g e v a r i a b l i t y i m p l i e s t h a t , w h i l e a t l e a s t a t w o - f o l d i n c r e a s e i n t e r m i n a l h a l f - l i f e may be expected i n a uremic s u b j e c t , s u b s t a n t i a l l y l o n g e r h a l f - l i v e s may be encountered and e x c e s s i v e drug accumulation may occur on m u l t i p l e d o s i n g even wi t h reduced doses. The p a t t e r n o f the plasma c o n c e n t r a t i o n s e n t e r i n g and l e a v i n g the d i a l y s e r appear t o behave i n a somewhat u n p r e d i c t a b l e manner w i t h "venous" c o n c e n t r a t i o n s sometimes exceeding th e " a r t e r i a l " c o n c e n t r a t i o n s . Two p o s s i b l e e x p l a n a t i o n s may r a t i o n a l i z e t h i s problem. F i r s t , s i n c e the removal o f MCP by h e m o d i a l y s i s i s r e l a t i v e l y i n e f f i c i e n t , a r e l a t i v e l y l a r g e amount of water may be removed from the plasma thereby c o n c e n t r a t i n g the MCP and making the "venous" c o n c e n t r a t i o n appear h i g h e r than the " a r t e r i a l " c o n c e n t r a t i o n . The second e x p l a n a t i o n may be t h a t MCP adheres t o some component o f the a r t i f i c i a l kidney o r t u b i n g and l e a c h e s back i n t o the plasma as d i a l y s i s p r o g r e s s e s . Given the v a r i a b i l i t y of the k i n e t i c s o f MCP, r i g i d d o s i n g g u i d e l i n e s f o r use i n r e n a l f a i l u r e may be i n a p p r o p r i a t e . F o l l o w i n g a normal l o a d i n g dose, a maintenance dose r e d u c t i o n of a t l e a s t 50 % w h i l e m a i n t a i n i n g the d o s i n g i n t e r v a l (tau) may p r e v e n t both the accumulation o f MCP and adverse e f f e c t s noted w i t h the i n i t a l h i g h c o n c e n t r a t i o n s soon a f t e r d o s i n g . The e x t r a c t i o n r a t i o s (E) and d i a l y s e r c l e a r a n c e s (Cld) c a l c u l a t e d suggest t h a t h e m o d i a l y s i s does not c o n t r i b u t e s i g n i f i c a n t l y t o the removal of MCP from uremic p a t i e n t s . No s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e s were noted i n these two parameters between the two a d m i n i s t r a t i o n s of MCP. The l a c k of removal of MCP by d i a l y s i s p r o b a b l y i s due t o the h i g h volume o f d i s t r i b u t i o n of t h i s drug. The r e l a t i v e l y low c o n c e n t r a t i o n of MCP i n plasma may not p r o v i d e a l a r g e enough c o n c e n t r a t i o n g r a d i e n t t o p r o v i d e an adequate d r i v i n g f o r c e f o r d i f f u s i o n . There are no s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e s between any of the pharmacokinetic parameters between the two a d m i n i s t r a t i o n s of MCP although some i n t r a - i n d i v i d u a l v a r i a t i o n was noted. T h i s suggests t h a t h e m o d i a l y s i s has no e f f e c t on t h e k i n e t i c s d i s p l a y e d subsequent t o i t s t e r m i n a t i o n . The r e s u l t s observed from the kidney t r a n s p l a n t r e c i p i e n t p r o v i d e some i n t e r e s t i n g i n f o r m a t i o n f o r s p e c u l a t i o n . The k i n e t i c s w h i l e the p a t i e n t was uremic show the t y p i c a l p a t t e r n o f d i m i n i s h e d t o t a l body c l e a r a n c e w i t h extended plasma h a l f - l i f e . However, f o l l o w i n g the kidney t r a n s p l a n t the k i n e t i c parameters r e v e r t t o w i t h i n a p p a r a n t l y normal l i m i t s on both subsequent a d m i n i s t r a t i o n s . On the second a d m i n i s t r a t i o n f o l l o w i n g the t r a n s p l a n t , 3 months f o l l o w i n g surgery, t h e r e appears t o be a f u r t h e r improvement i n t o t a l body c l e a r a n c e . T h i s may be r e l a t e d t o an i n c r e a s e d volume o f d i s t r i b u t i o n s i n c e the h a l f - l i f e i s r e l a t i v e l y unchanged and the p a t i e n t s ' body weight had i n c r e a s e d . The r a p i d change i n k i n e t i c s suggests t h a t the d e f i c i t i n t o t a l body c l e a r a n c e c r e a t e d by uremia i s not due t o an i r r e v e r s i b l e e f f e c t . The exact mechanism r e s p o n s i b l e f o r the k i n e t i c changes i n uremia cannot be e l u c i d a t e d from the data a v a i l a b l e . S e v e r a l p o s s i b i l i t i e s e x i s t however. E x t r a h e p a t i c metabolism does not seem l i k e l y . K a p i l e t  a l . (1984) showed t h a t the kidney, and lung t i s s u e s do not c o n t r i b u t e t o the metabolism of MCP i n the r a t . The f i n d i n g s i n the r a t may not be d i r e c t l y e x t r a p o l a t a b l e t o man due t o the m e t a b o l i c d i f f e r e n c e s between the two s p e c i e s . R e c i r c u l a t i o n of the conjugates o f MCP may occur. In t h i s case the s u l p h a t e conjugate, which accounts f o r -40 % would have t o be e x c r e t e d i n the b i l e , deconjugated and then reabsorbed. In g e n e r a l , t h i s p r o c e s s i s accepted t o occur f o r the g l u c u r o n i d e conjugates o f some drugs (Verbeeck, 1982) but does not appear t o have been r e p o r t e d f o r s u l p h a t e c o n j u g a t e s . In a d d i t i o n , the s u l p h a t e conjugate of MCP appears t o be r e l a t i v e l y c h e m i c a l l y s t a b l e . H y d r o l y s i s o c c u r s w i t h i n 15 minutes a t 100 °C i n the presence of 1 N h y d r o c h l o r i c a c i d ( A r i t a e t a l . f 1970). There does not appear t o be any evidence o f r e c i r c u l a t i o n i n the plasma c o n c e n t r a t i o n vs time p r o f i l e s o b t a i n e d from the uremic v o l u n t e e r s . Thus, such a r e c i r c u l a t i o n p r o c e s s would have t o occur a t a somewhat c o n s t a n t r a t e which i s a t odds w i t h the accepted p a t t e r n of b i l i a r y r e c y c l i n g . A more p l a u s i b l e e x p l a n a t i o n may be a change i n h e p a t i c MCP metabolism secondary t o c h r o n i c r e n a l f a i l u r e . Although a d i r e c t e f f e c t on the s u l p h a t i o n of MCP may be p o s s i b l e , i t has g e n e r a l l y been accepted t h a t t h i s c o n j u g a t i o n pathway i s r e l a t i v e l y u n a f f e c t e d by uremia (Reidenberg, 1977). T h i s assumption i s made on data d e r i v e d from the k i n e t i c s o f acetaminophen where, although the g l u c u r o n i d e and s u l p h a t e conjugates accumulated i n uremia, the k i n e t i c s o f the p a r e n t drug were u n a l t e r e d from those seen i n h e a l t h y v o l u n t e e r s (Lowenthal e t a l • f 1976). However, the e x i s t e n c e of s e v e r a l s u l p h o t r a n s f e r s e s , w i t h some degree o f s u b s t r a t e s p e c i f i c i t y , e x i s t (Pang, 1982). I t may be p o s s i b l e t h a t the enzymes r e s p o n s i b l e f o r the s u l p h a t i o n o f MCP may be s e n s i t i v e t o the sequelae o f uremia. Yet, f o r MCP, t h i s a l t e r a t i o n may be r e v e r s i b l e as evidenced by the change i n k i n e t i c s f o l l o w i n g kidney t r a n s p l a n t . I t has been shown t h a t the r a t e o f removal by t h e l i v e r f o r o r g a n i c anions such as i n d o c y a n i n e green and h i p p u r a t e i s decreased from t h a t seen i n normal l i v e r s (Yates e t aL.. 1984). These authors suggested t h a t the decrease i n removal was not the r e s u l t o f a c o m p e t i t i o n f o r uptake i n t o the l i v e r between th e s u b s t r a t e and some component of uremic plasma but c o u l d not s p e c i f y the r e s p o n s i b l e mechanism. S i m i l a r data f o r o r g a n i c c a t i o n s does not appear t o be a v a i l a b l e (Gibson, 1986). Terao and Shen (1985) demonstrated t h a t some component o f uremic r a t plasma i n h i b i t s e x t r a c t i o n o f 1 - p r o p r a n o l o l i n the i s o l a t e d p e r f u s e d r a t l i v e r . A lthough p r o p r a n o l o l and MCP are s t r u c t u r a l l y u n r e l a t e d , i t may be p o s s i b l e t h a t a s i m i l a r p r o c e s s may occur. However, as evidenced by the c o n s t a n t v a l u e s o f the k i n e t i c parameters r e l a t i v e t o the time o f onset of h e m o d i a l y s i s , i f such a substance i m p a i r s MCP c l e a r a n c e i t i s not hemodialysable. A l t e r n a t i v e l y , o r a d d i t i o n a l l y a change i n h e p a t i c b l o o d flow secondary t o the sequelae of uremia may a l t e r MCP k i n e t i c s . S i n c e MCP appears t o be a drug w i t h i n t e r m e d i a t e o r h i g h c l e a r a n c e , i t s k i n e t i c s are a t l e a s t p a r t i a l l y a f u n c t i o n o f l i v e r b l o o d flow ( W i l k i n s o n and Shand, 1975). Although uremia may not i n i t s e l f cause changes i n l i v e r b l o o d flow, s e v e r a l a t t e n d e n t c o m p l i c a t i o n s of uremia, f o r example h y p e r t e n s i o n and c a r d i a c d i s e a s e , may a l t e r h e p a t i c p e r f u s i o n and induce changes i n drug c l e a r a n c e (George, 1979) . While the change i n h e p a t i c b l o o d flow may not be a b l e t o account f o r the e n t i r e change i n MCP k i n e t i c s i t may o f f e r , a t l e a s t a p a r t i a l e x p l a n a t i o n . 5. SUMMARY AND CONCLUSIONS 1) Metoclopramide undergoes l i n e a r k i n e t i c s i n normal, h e a l t h y v o l u n t e e r s a t doses between 5 and 20 mg. 2) The a b s o l u t e b i o a v a i l a b i l i t y o f MCP i s -0.78 + and the r e l a t i v e b i o a v a i l a b i l i t y o f the s o l u t i o n and t a b l e t i s ~ 1.00. 3) In s p i t e o f the r e l a t i v e l y minor c o n t r i b u t i o n o f r e n a l c l e a r a n c e t o t o t a l body c l e a r a n c e i n normals, metoclopramide k i n e t i c s are s u b s t a n t i a l l y a l t e r e d i n uremia v i z a decrease i n t o t a l body c l e a r a n c e o f a t l e a s t t w o - f o l d w i t h an atte n d e n t p r o p o r t i o n a t e i n c r e a s e i n e l i m i n a t i o n h a l f - l i f e and l i t t l e o r no change i n volume of d i s t r i b u t i o n . 4) H emodialysis i s i n e f f e c t i v e a t removing metoclopramide from the body. 5) H e m o d i a l y s i s has no e f f e c t on the apparent k i n e t i c parameters f o l l o w i n g i t s t e r m i n a t i o n . 6) F o l l o w i n g kidney t r a n s p l a n t a t i o n t h e r e appears t o be a r a p i d r e v e r s i o n t o a p p a r e n t l y normal k i n e t i c s from the uremic s t a t e . 6. 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Biochem Pharmacol. 3_3, 1695. 7.APPENDIX PATIENT MEDICATIONS PB 2, 3, 4, 6, 11, 21, 22 WL 1, 3, 8, 11, 12b BM 3, 5, 9, 10, 12a, 18 GM 1» 3, 5, 7, 11, 12a, 13, 17 JS 1, 3, 5, 9, 12a, 13 SS 2, 3, 10, 12a, 15, 19, 20 JT 1, 3, 5, 11 RT If 3, 8, 14 1. Z-Bec ( m u l t i v i t a m i n ) 2. Beminal c F o r t i s ( m u l t i v i t a m i n ) 3. F o l i c a c i d 4. B i o t i n 5. V i t a m i n D 6. Calcium L a c t a t e 7. I r o n Dextran 8. Amphojel Suspension (A10H ) 9. Amphojel T a b l e t s (A10H ) 3 10. Robalate (dihydroxyaluminium acetate) 11. B a s a l g e l (A10H ) 12. Docusate Sodium a) Colace b) Regulex 13. B i s a c o d y l 14. P i n d o l o l 15. P r o p r a n o l o l 16. M e t o p r o l o l 17. Diazepam 18. S e c o b a r b i t a l 19. C e p h l e x i n 20. C a p t o p r i l 21. S u l f a s o x a z o l e 22. Phenytoin Na 

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