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

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METOCLOPRAMIDE DISPOSITION I N NORMAL AND UREMIC HUMANS by MATTHEW ROWLAND WRIGHT B.Sc.(Pharm.); U n i v e r s i t y  of British  Columbia,  1985  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS OF THE DEGREE OF MASTER OF SCIENCE  in THE FACULTY OF GRADUATE STUDIES (Faculty o f Pharmaceutical Sciences) D i v i s i o n o f Pharmaceutics We a c c e p t t h i s t h e s i s a s c o n f o r m i n g to the required standard  THE UNIVERSITY OF BRITISH COLUMBIA J u n e 1987 (c)  Matthew R o w l a n d W r i g h t , 1987  In  presenting  degree  this  at the  thesis  in  partial fulfilment  of  University of  British Columbia,  I agree  freely available for reference copying  of  department publication  this or of  thesis by  this  his  for or  and study.  Department The University of British Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3  DE-6(3/81)  that the  representatives.  may be It  thesis for financial gain shall not  permission.  requirements  I further agree  scholarly purposes her  the  for  an  advanced  Library shall make it  that permission  for extensive  granted  head  is  by the  understood be  that  allowed without  of  my  copying  or  my written  ABSTRACT Metoclopramide  (MCP)  i s a potent  antinauseant/  a n t i e m e t i c and  gastrointestinal motility modifier.  finds c l i n i c a l  use  administered  on b o t h  This thesis both  i n a wide v a r i e t y an  acute  and  of s i t u a t i o n s  n o r m a l , h e a l t h y v o l u n t e e r s and  and  kinetics, effects  the e f f e c t s  the  program.  Specifically,  of hemodialysis  B a s e d on were c l a i m e d  early t o be  bioavailability these  early  the  v o l u n t e e r s we  20  d o s e - d e p e n d e n t and  extremely  kinetics mg,  the  relative tablet  variable.  the  credibility  find, o f MCP  study  of t h e i r involving  linear  over  absolute b i o a v a i l a b i l i t y  bioavailability  dosage form  MCP  examined.  of  MCP  absolute  However, many o f  findings.  problems Based  s i x normal,  i n contrast to previous are  In  the  reports, the pharmacokinetics  four-way c r o s s o v e r  the  are  on  and  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  which l i m i t a  kinetics  i n the  a r e examined.  by h e m o d i a l y s i s ,  on MCP  on  and  of chronic r e n a l f a i l u r e  r e m o v a l o f MCP  in  i n uremic subjects  relative bioavailabilities  the uremics,  is  o f MCP  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 , absolute  and  chronic basis.  examines t h e p h a r m a c o k i n e t i c s  a maintenance hemodialysis  MCP  on  healthy  results,  that  the dose range of 5 and  the  o f a s o l u t i o n dosage form vs  the  i s approximately  i s 76  1.  + 38  %,  -  ii i  Although renal % of the total has been  body c l e a r a n c e  o f MCP  proportional  insignificant  Hemodialysis  about  i n normals,  20  uremia  kinetics i n  T h e r e a p p e a r s t o be a t l e a s t a  decrease i n t o t a l  attendent, and  accounts f o r only  shown t o s u b s t a n t i a l l y a l t e r MCP  b o t h r a t a n d man. two-fold  clearance  body c l e a r a n c e  increase  w i t h an  i n elimination  half-life  change i n volume o f d i s t r i b u t i o n .  i s relatively  ineffective i n clearing  MCP  from t h e 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 to the r e l a t i v e l y  l a r g e v o l u m e o f d i s t r i b u t i o n o f MCP.  H e m o d i a l y s i s a l s o h a s no e f f e c t s on t h e a p p a r e n t k i n e t i c parameters results  following  i t s termination.  f r o m a s i n g l e p a t i e n t who  transplant accompanied  show t h a t  received  t h e renewed r e n a l  by an a p p a r e n t r e v e r s i o n  parameters t o w i t h i n transplantation.  In addition,  normal  a kidney  function i s  of a l l kinetic  limits within  15 d a y s o f  iv  TABLE OF CONTENTS CHAPTER  PAGE ABSTRACT  i i  L I S T OF TABLES  v i i  L I S T OF FIGURES  viii  L I S T OF SCHEMES  x  ABBREVIATIONS  xi  ACKNOWLEDGEMENTS  xiv  1  INTRODUCTION  1  1.1  Metoclopramide Pharmacology Applications  1.2  E f f e c t o f Route o f A d m i n i s t r a t i o n Pharmacokinetics  1.3  Dose-linearity  1.4  E f f e c t s of Chronic Renal F a i l u r e Pharmacokinetics  and C l i n i c a l on  of Kinetics  1 8 12  on  14  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  Distribution  17  1.4.3  Metabolism  1.4.4  Elimination of Intact Metabolites  and P r o t e i n  Binding  20 Drug  and  22  1.5  I n f l u e n c e o f H e m o d i a l y s i s on D r u g Removal  25  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 2.1.2 2.1.3 2.1.4 2.1.5  Chemicals Reagents Solvents Gases S u p p l i e s f o r human e x p e r i m e n t s  34 34 35 35 35  2.2  Equipment  36  2.3  Preparation of Solutions  37  2.3.1 2.3.2  Metoclopramide.HCl.H 0 Maprotaline.HCl (internal  2.3.3  Reagent s o l u t i o n s  2.4  Sample E x t r a c t i o n 2.4.1 2.4.2  2.5 2.6 2.6.1 2.6.2  Pharmacokinetic Humans  2.7.4 2.7.5 2.7.6 Data 2.8.1 2.8.2 2.8.3 3  3.1  Silica  38 39 41 41  plasma  41 42  S t u d i e s i n N o r m a l a n d U r e m i c 42  Experimental p r o t o c o l i n normal, h e a l t h y volunteers. Q u a n t i t a t i v e plasma a n a l y s i s i n normals Experimental p r o t o c o l i n uremic volunteers Q u a n t i t a t i v e plasma a n a l y s i s i n uremics Experimental protocol i n kidney transplant recipient Q u a n t i t a t i v e plasma a n a l y s i s i n kidney transplant recipient  2.7.2 2.7.3  2.8  38  GC-ECD  GC-ECD P a r a m e t e r s A p p l i c a t i o n o f assay t o uremic  2.7.1  38  Procedure  Plasma e x t r a c t i o n Derivatization Standard Curve P r e p a r a t i o n f o r Fused C a p i l l a r y GC-ECD A n a l y s i s Capillary  2.7  standard)  37 37  42 46 46 49 49 50  Analysis  50  Computer f i t t i n g Pharmacokinetic c a l c u l a t i o n s Statistical tests  50 51 52  RESULTS Applicablity  53 o f assay t o uremic  serum.  53  vi  3.1.1 3.1.2 3.2  E x t r a c t i o n o f b l a n k plasma Standard curve Normal p h a r m a c o k i n e t i c s  53 53 56  3.2.1  Plasma K i n e t i c s  56  3.2.2  Urinary Excretion  60  3.3  Uremic 3.3.1 3.3.2  3.4  pharmacokinetics  24 h o u r p r e d i a l y s i s d o s e 1 hour p r e d i a l y s i s dose Pharmacokinetics i n kidney t r a n s p l a n t recipient  62 62 68 68  3.4.1  Plasma K i n e t i c s  68  3.4.2  Urinary Excretion  74  4  DISCUSSION  77  4.1  Applicability  4.2  Normal  Pharmacokinetics  78  4.3  Uremic Pharmacokinetics  89  5  SUMMARY AND  99  6  REFERENCES  100  7  APPENDIX  116  o f Assay  CONCLUSIONS  t o Uremic Plasma  77  vii  L I S T OF  TABLES  TABLE  PAGE  1  Factors affecting  2  Metoclopramide k i n e t i c parameters o b t a i n e d from plasma o f h e a l t h y v o l u n t e e r s  57  3  Metoclopramide pharmacokinetic parameters , o b t a i n e d from u r i n e d a t a o f h e a l t h y volunteers  63  4  Metoclopramide k i n e t i c parameters from t h e c u m u l a t e d u r i n e and p l a s m a r e s u l t s o f t h e normal, h e a l t h y v o l u n t e e r s  64  5  Clinical  65  6  Details pertaining to the d i a l y s i s of the uremic p a t i e n t s .  66  7  Metoclopramide pharmacokinetic parameters f r o m u r e m i c v o l u n t e e r s 24 h p r i o r t o dialysis.  67  8  Metoclopramide pharmacokinetic parameters 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 .  70  9  C l i n i c a l p a r a m e t e r s f o r u r e m i c p a t i e n t BM b e f o r e and a f t e r k i d n e y t r a n s p l a n t a t i o n .  72  details  drug b i o a v a i l a b i l i t y  of uremic p a t i e n t s  10  10  Metoclopramide pharmacokinetic parameters f o r u r e m i c v o l u n t e e r BM b e f o r e a n d a f t e r kidney t r a n s p l a n t a t i o n .  75  11  Metoclopramide Pharmacokinetic parameters from t h e u r i n e o f t h e k i d n e y t r a n s p l a n t recipient  76  vi i i  L I S T OF  FIGURES  FIGURE  PAGE  1  Stucture of Metoclopramide  2  Dettli  3  Representative  Nomogram  Uremic Blank 4  Standard  5  Mean A r e a vs  6  Plasma  Concentration 58  mg  5 mg  (•—•)  , 20  O r a l S o l u t i o n (0—0)  mg  5 mg  (•—•)  Time P r o f i l e  be  for a Single,  Healthy  mg  O r a l S o l u t i o n (•— •)  Plasma C o n c e n t r a t i o n  f o r a 10 mg  a Uremic Volunteer  Hemodialysis.  59  O r a l S o l u t i o n ( o — o) ,  , 2 0 mg  Representative  IV  Amount R e m a i n i n g t o  O r a l S o l u t i o n (•—o) , 10  Bolus  ,  O r a l S o l u t i o n (•—«)  i n the Urine  Volunteer.  vs  Healthy  O r a l S o l u t i o n (o—n) , 10 mg  Excreted  10 mg  Plasma C o n c e n t r a t i o n for a Single  Representative  to  Plasma  Time C u r v e  Bolus  8  55  Under the  Volunteer.  IV  54  Curve  Time P r o f i l e s  7  24 Chromatograms o f E x t r a c t e d  Representative  10  1  24  IV B o l u s h Prior  61  vs  Dose  Given  to 69  Prior  to Dialysis  concentration ( D - D )  to  — •) , v e n o u s  arterial  concentration  .  Representative Time  , Dialysis;  Plasma C o n c e n t r a t i o n  P r o f i l e f o r a 10 mg  I V B o l u s Dose  1 h Prior  a Uremic Volunteer  vs Given  to  Hemodialysis. Prior  to Dialysis  concentration ( D — D )  (•-•), D i a l y s i s ;  (•—•) , v e n o u s  concentration  ,  Post-dialysis  (o—o) •  Plasma C o n c e n t r a t i o n Kidney Transplant IV  arterial  B o l u s Dose.  Transplant  v s Time P r o f i l e s  Recipient Following  Uremia  (• —•) , 15 d a y s  (o—o) , 3 months A f t e r  f o r the 10  mg  After  Transplant  X  L I S T 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 H e a 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  xi  ABBREVIATIONS AAG  Alpha-l-Acid  A.D.M.E.  Absorption,  Glycoprotein Distribution,  Metabolism, Alk  Phos  ARE  Alkaline  Elimination  Phosphatase  Amount R e m a i n i n g t o b e Excreted  ANOVA  Analysis  of Variance  AUC  Area Under t h e Plasma C o n c e n t r a t i o n v s Time Curve  A-V  Arterio-venous  BUN  Blood Urea  Cld  Dialyser  Clint  Intrinsic  CRTZ  Chemoreceptor T r i g g e r  CV.  Coefficient of Variation  E  Extraction Efficiency  ECD  Electron  Nitrogen  Clearance Clearance  Capture  Detection  F  Bioavailability  FID  Flame I o n i z a t i o n  g  Acceleration  GC-ECD  Gas C h r o m a t o g r a p h i c Capture  GI HFB  Zone  Detection  due t o g r a v i t y  Detection  Gastrointestinal Heptafluorobutyryl  Electron  HFB-MAP  Heptafluourobutyryl of  HFB-MCP  derivative  maprotaline  Heptafluorobutyryl  derivative  t  of I.D.  metoclopramide  Internal  Diameter  IV  Intravenous  Ka  Absorption rate Terminal  K  n  o  r  K  Constant  E l i m i n a t i o n Rate  E Constant Lower E s o p h a g e a l  LES  Maprotaline  MAP.HCl  Sphincter  Hydrochloride  Metoclopramide  MCP MCP.HCl MCP.HC1.H 0  Metoclopramide  Hydrochloride  Metoclopramide  Hydrochlor-  2  ide r  Monohydrate  2  RBC Scr o r s.d. o r s t d dev SGOT  Coefficient Red  Blood  o f Determination  Cell  Serum C r e a t i n i n e Standard d e v i a t i o n Serum G l u t a m a t e  Oxalate  Transaminase SGPT  Serum G l u t a m a t e Transaminase  Pyruvate  Elimination  half-life  Volume o f D i s t r i b u t i o n Volume o f t h e C e n t r a l Compartment  ACKNOWLEDGEMENTS The for  author i s deeply  h i s encouragement,  course Price  o f t h i s work.  indebted  t o D r . James  f r i e n d s h i p , and s u p p o r t  Axelson during the  S i n c e r e thanks a l s o t o Dr. John  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 during Abbott,  this project.  Dr. John S i n c l a i r ,  Thanks a l s o t o Dr. Frank  a n d D r . 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,  Wayne R i g g s Also and  a n d f r i e n d s h i p o f Mr.  i s greatly appreciated  t h e support  assistance during  patience, greatly  The  much  t h e human  appreciated.  experimentation,  and f r i e n d s h i p o f Mrs. B a r b a r a M c E r l a n e a r e  appreciated.  A l s o t h e d e d i c a t i o n and a s s i s t a n c e  o f Ms. N o r a Wong, d u r i n g warmly  recognized.  a n d e n c o u r a g e m e n t o f Mr. Sun Dong Yoo  Ms. G r a c e L a p - Y u Chan a r e v e r y The  and warmly  t h e uremic v o l u n t e e r  studies are  recognized. author  studentship  i s a l s o g r a t e f u l t o MRC  awarded h i m .  f o r the  the memory o f my g r a n d f a t h e r ,  Rev. K. S t . C. Thomas.  1  1. 1.1  INTRODUCTION  Metoclopramide Pharmacology  and  Clinical  Applications  Introduction heterocyclic  o f a methoxy g r o u p o n t o t h e  r i n g o f p r o c a i n a m i d e p r o d u c e s compounds w i t h  antiemetic  activity  ( C l i n t o n and L a s k o w s k y ,  antiemetic  activity  o f t h e s e c o n g e n e r s c a n be e n h a n c e d  the  addition  1955).  The  o f a h a l o g e n atom p a r a t o t h e methoxy  (Besancon e t a l . , 1964).  by  group  Metoclopramide i s the  2-methoxy, 5 - c h l o r o a n a l o g u e o f p r o c a i n a m i d e ( s e e  Figure  1) •  Figure  1:  Metoclopramide  The p h a r m a c o l o g y metoclopramide several 1983;  (MCP)  and c l i n i c a l have been  authors (Pinder  Albibi  p r o c a i n a m i d e , MCP  extensively  e t a l . , 1976;  and McCallum,  Desmond and Watson,  applications  1986).  1983;  of  r e v i e w e d by  Harrington e ta l . ,  Shaughnessy,  1985;  A l t h o u g h i t i s an a n a l o g o f  does n o t p o s s e s s s i g n i f i c a n t  2  antiarrhytmic et  or local  a l . . 1983).  oral  properties  The p h a r m a c o l o g i c a l  most p r o n o u n c e d generalized  anaesthetic  a c t i o n s o f MCP  or intravenous  in motility  i s seen a f t e r e i t h e r  administration  (Pinder  the  I n t h e esophagus,  Brock-Utne  well  (LES),  has  in a  with  i n p r e g n a n t women 1976;  I n a d d i t i o n , MCP  a m p l i t u d e and d u r a t i o n  of  dose-dependent  B e h a r and B i a n c a n i a ,  e t a l . . 1978).  several  and p a t i e n t s  and t o a l e s s e r e x t e n t  (Baumann e t a l . . 1979;  MCP  r a i s e s the pressure  i n both normal v o l u n t e e r s  hiatus hernia  the  MCP  lower esophageal s p h i n c t e r  fashion,  e t a l . . 1976;  1981).  Segmentally, w i t h i n the Gl t r a c t , effects.  are  i n t h e g a s t r o i n t e s t i n a l t r a c t where a  increase  Schulze-Delrieu,  (Harrington  also  enhances  of esophageal p e r i s t a l s i s  as i m p r o v i n g a c i d c l e a r a n c e  (Desmond a n d Watson, 1 9 8 6 ) .  MCP  from t h e  as  esophagus  significantly  a c c e l e r a t e s g a s t r i c e m p t y i n g and t h e a m p l i t u d e o f g a s t r i c contraction MCP  (Harrington  on t h e s t o m a c h  e t a l . . 1983).  rates or small  and d u o d e n a l c o n t r a c t i o n s  antral  (Pinder  (Harrington  coordination  e t a l . . 1983).  o f a n t r a l and d u o d e n a l  of g a s t r i c a c i d secreted  MCP  The  a r e on t h e  induces c o n t r a c t i o n as w e l l  e t a l . . 1976).  with  and/or slow a n t r a l  e f f e c t s w i t h i n t h e stomach  r e g i o n where MCP  improving  e f f e c t s of  a r e most r e a d i l y s e e n i n p a t i e n t s  slow g a s t r i c emptying  most p r o n o u n c e d  The  as  contraction  h a s no e f f e c t s on t h e amount  o r on serum  gastrin  levels  (Cohen e t a l . . 1 9 7 6 ) . decreases  intestinal  In the small transit  intestine,  MCP  time v i a a s t i m u l a t i o n o f  smooth m u s c l e c o n t r a c t i o n w h i c h c a n b e a n t a g o n i z e d b y anticholinergic  agents  (Pinder  improvement o f a n t r a l / d u o d e n a l and  an i n c r e a s e  has  been noted  be  a stronger  stimulant bromide  Although a stimulant contraction muscle  f  1976).  contraction  of intestinal (Oigaard  contraction  MCP a p p e a r s t o  motility  than i s  and F l e c k e n s t e i n ,  1975).  o f b o t h a m p l i t u d e and f r e q u e n c y o f  in in vitro  strips  (Schulze-Delrieu,  MCP on t h e l a r g e  e t a l . . 1983).  As w e l l ,  coordination  i n t h e amplitude o f duodenal (Harrington  pyridostigmine  et a l .  of colonic circular  1 9 7 9 ) , no c o n s i s t e n t  smooth  effects of  i n t e s t i n e have been demonstrated  (Harrington  e t a l . , 1983).  No c o n s i s t a n t  on  bladder  i n a n i m a l s o r humans h a v e  the g a l l  been noted  The unclear.  (Pinder  exact  i n vivo  mechanism o f MCP a c t i o n  agents  (Harrington  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  not  i n f l u e n c e d by g a n g l i o n i c 1976).  Since  the  site  of action  the  peripheral  i n t h e GI t r a c t i s  a r e i n h i b i t e d by  has  al..  o f MCP  e t a l . . 1976).  However, many a c t i o n s  anticholinergic  effects  i n vivo  e t a l . , 1983).  and i t s a c t i o n s a r e  blocking  agents  (Pinder e t  vagotomy d o e s n o t a f f e c t MCP i n t h e GI t r a c t  MCP  activity,  i s thought t o be a t  n e r v e e n d i n g s i n t h e g u t smooth m u s c l e  ( S t a d a a s a n d Aune, 1 9 7 1 ) .  There a r e three  proposed  4  mechanisms u s e d t o  explain  the  activity  o f MCP  i n the  GI  i n the  manner  of  o f MCP  are  tract: 1.  Potentiation  of  A l t h o u g h MCP traditional  cholinergic  i s not  cholinomimetic  cholinergic agonists,  a n t a g o n i z e d by  1986).  c h o l i n e r g i c neurons  Using the  the  within  release the  of  acetylcholine  isolated  human and  that  augments a c e t y l c h o l i n e  MCP  muscarinic  2.  receptors  (Beani et  stores  Further evidence  smooth m u s c l e release  Man  and  from  suggests  sensitizes  a l . , 1970).  Dopamine A n t a g o n i s m Dopamine i s w e l l  known t o be  the  central, peripheral,  and  MCP  has  able  b e e n shown t o be  a neurotransmitter  e n t e r i c nervous to  antagonize  m e d i a t e d d e l a y s o f g a s t r i c e m p t y i n g and a n t a g o n i z e s MCP and  and  i s dependent  from n e u r o n a l  g u i n e a p i g GI  on  Watson,  s t o m a c h Hay  activity  e n t e r i c nervous system.  (Stadaas  depends  (Desmond and  MCP  1968).  activity  activity  i s o l a t e d guinea p i g  (1979) h a v e d e m o n s t r a t e d t h a t on  (Eisner,  a b o l i s h MCP  Aune, 1 9 7 1 ) , s u g g e s t i n g t h a t  intramural  many a c t i o n s  a n t i c h o l i n e r g i c agents  Vagotomy, however, d o e s n o t and  activity  McCallum,  induced 1980;  increases  Baumann e t  i n LES  in  systems. L-dopa  L-dopa tone  a l . , 1979).  (Berkowitz  5  3.  D i r e c t A c t i o n on Smooth M u s c l e I n an i n v i t r o p r e p a r a t i o n  muscle,  i n tension  (Cohen a n d D i M a r i n o ,  Although tenuous, t h i s  observation  1976).  suggests that  on t h e GI t r a c t ,  possesses c e n t r a l e f f e c t s that are l i k e l y overall  motility raise  some  a c t i o n o f MCP may b e 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  its  esophageal  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  increases  direct  o f oppossum  antiemetic  efficacy  MCP  as important  a s t h e i n c r e a s e d GI t r a c t  (Desmond and Watson, 1 9 8 6 ) .  MCP  i s believed to  t h e t h r e s h o l d o f t h e chemoreceptor t r i g g e r  (CRTZ) a n d d e c r e a s e t h e s e n s i t i v i t y which p r o j e c t t o t h e emetic centre reticular  formation  stimulation  of visceral  zone afferents  i n the lateral  (Pinder e t a l . . 1976).  o f t h e CRTZ i s r e l a t i v e l y  Since  specific to  dopamine a g o n i s t i c d r u g s , c e n t r a l l y  a c t i n g agents  block  t o be dopamine  this  are generally considered  antagonists  (Cannon,  behavioural  effects  consistent with antagonist  1975).  MCP a l s o  which  demonstrates  i n a n i m a l s and a d v e r s e e f f e c t s  the proposition that  (Harrington  Jenner e t a l .  (1978) h a v e d e t e r m i n e d t h a t t h e b e n z a m i d e s i n t e r a c t  MCP may b e c l a s s i f i e d antagonist.  dopamine r e c e p t o r ,  as a s e l e c t i v e  i n man  i t i s a dopamine  e t a l . . 1983) .  a non-adenylate cyclase coupled  to  D-2  receptor  with thus  6  S i n c e MCP to  affect  i s a dopamine a n t a g o n i s t  the  r e l e a s e o f v a r i o u s hormones.  stimulates prolactin increasing  levels  MCP  luteinizing levels  hormone, and  (Desmond and  procainamide,  reported  MCP,  d e c r e a s e r e n a l plasma et  a l . , 1986)  al.  by  e t a l . . 1983).  crisis  under  however, h a s  MCP  has  s e t t i n g s both  i n the  found c l i n i c a l i n E u r o p e and  1983;  1976,  Harrington  Shaughnessy,  with  have been to (Israel  A l t e r n a t i v e l y , Tarn i n hepatic blood  et flow,  rat.  use  i n a wide v a r i e t y o f  North America.  e t a l . . 1983;  1985;  in  However,  been r e p o r t e d  r e v i e w s have e x t e n s i v e l y examined t h e s e al..  on  conduction  i n oncology p a t i e n t s  l e s s t h a n 20%.  MCP,  effects  in patients  (1981) d e m o n s t r a t e d a d e c r e a s e  b r o u g h t a b o u t by  hormone  general  c a r d i a c arrhythmias  flow  In  related to  of hypotension  hypertensive  i n man.  arginine  1986).  have s i g n i f i c a n t  (Harrington  p h e o c h r o m o c y t o m a , and  and  i n g r o w t h hormone,  intracardiac electrical  instances  anaesthesia,  Watson,  is structurally  or  studies  isolated  slightly  Watson, 1 9 8 6 ) .  reductions  able  MCP  follicle-stimulating  i t does not  pressure  animal  (Desmond and  causes s l i g h t  A l t h o u g h MCP  blood  r e l e a s e as w e l l as  serum t h y r o t r o p i n , a l d o s t e r o n e ,  vasopressin contrast,  i t i s also  Desmond and  Several  uses  Albibi  (Pinder  and  Watson,  et  McCallum,  1986).  MCP  has  found use  resulting  in controlling  MCP  and  associated with  vomiting  postoperative  radiation  i s effective  patients  (Assaf  particular  Lean,  sickness  uremia  (Jones,  (Harrington  (Ward, 1 9 7 3 ) , and has  r e f l u x treatment  or diabetes therapy  antimigrainous and  radiological  James and  procedures  i n d u c t i o n as  (Schulze-^Delrieu, examined the treatment  in  1981) .  (Harrington  some o f t h e  (in  pregnancy  (Singh  in  (Harrington  et a l . ,  vagotomy and  Watson,  and  gastric  1986),  1 9 7 4 ) , GI  tract  ( C h r i s t i e and  diagnostic  Ament, prior  to  emergency c a e s a r i a n  Furthermore,  other  1976;  section  trials  in defective  have  lactation,  hypomotile ureter, o r t h o s t a t i c  t a r d i v e d y s k i n e s i a , and  vertigo  e t a l . . 1983).  Adverse e f f e c t s reversible  in  d e l i v e r y of  e f f e c t i v e n e s s o f MCP  hiccups,  chemotherapy  significantly  of p a t i e n t s with  hypotension,  1983).  (Matts,  Hume, 1 9 6 8 ) , and  anaesthetic  1968),  found use  (Desmond and  t o enhance t h e  agents  nausea  e t a l . . 1983),  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 resection  the  ( P i n d e r e t a l . , 1976), n a r c o t i c  A d d i t i o n a l l y MCP  gastroesophageal  More  in controlling  e t a l . . 1974), c a n c e r  cis-platin)  1973).  migraine  vomiting  from a v a r i e t y of e t i o l o g i e s .  specifically  therapy  n a u s e a and  and  occur  o f MCP  generally transient  i n approximately  larger clinical  Several  are  surveys  p a t i e n t groups,  e.g.  11%  and  of patients i n  (Harrington uremics  and  et a l . ,  8  children,  a p p e a r t o be  a t somewhat h i g h e r r i s k  development of adverse  e f f e c t s t o MCP.  r e s t l e s s n e s s a p p e a r t o be occurring  i n a b o u t 10%  Drowsiness  t h e m o s t common s i d e  of patients while  occur  i n a b o u t 9%  al..  1983).  Other  side effects  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).  Effect  and  effects  extrapyramidal  side effects  1.2  f o r the  of patients (Harrington et appear t o occur  o f R o u t e o f A d m i n i s t r a t i o n on  in  less  Drug  Kinetics  B a s e d on several  sulfonamide  administered Dost  studies using p-aminohippuric antibacterials,  to experimental  (1958) and  Gladtke  acid  and  w h i c h were  animals  both  (1964) p r o p o s e d  a  IV and  orally,  relationship  b e t w e e n d o s e and  area under t h e plasma c o n c e n t r a t i o n vs  time  known a s  curve  areas".  (AUC)  T h i s "law"  m e t a b o l i s m and t h e AUC  the  liver  establish In  fact,  t h e AUC  of  corresponding  that, i f distribution,  p r o p o r t i o n a l t o t h e d o s e and  then  is  of the route of administration.  Unfortunately, proposition  suggested  law  excretion are f i r s t - o r d e r processes,  is directly  independent  "the  the drugs used  to formulate  are only n e g l i g i b l y  and  are not  such i t has  this  or slowly metabolized  r e p r e s e n t a t i v e o f enough d r u g s  a generality  ( H a r r i s and  Riegelman,  by to  1969).  become q u i t e c l e a r t h a t f o r many d r u g s  i s dependent not  o n l y upon t h e d o s e b u t  also  on  9  the  route of administration, physiological  experimental of the drug expressed simplest  animal, and  by  the term  T h i s concept  bioavailability,  t e r m s r e f e r s t o t h e r a t e and (Gibaldi  mentioned,  and  as  reaching the  both  physiological  i n the  Perrier,  systemic  1982).  circulation  of the drug  following table  in its  extent of  f a c t o r s of the t e s t  factors  i s best  which,  drug  As p r e v i o u s l y  i s somewhat i n t u i t i v e ,  drug  physico-chemical  and  the  the physico-chemical p r o p e r t i e s  dosage form.  absorption  outlined  and  factors of  t h e amount o f  i s affected animal  and  and  by the  dosage form,  (Riegelman  and  as  Rowland,  1973) .  The  most r e l i a b l e  i s made by  determination of  t h e c o m p a r i s o n o f t h e AUC's o f e q u a l  drug  to experimental  s u b j e c t s on  oral  and  For a drug  IV r o u t e s .  compartmental  F oral  B  Dose AUC  TV  V.  B  therefore:  displaying  Dose  V.  doses  a crossover basis  kinetics:  AUC  and  bioavailability  K IV K. n  n  oral  n  by  of  TABLE 1 Factors 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 (Riegelman and Rowland, 1973) P h y s i o l o g i c a l FactorB  Dosage Form Factors  Properties of lumenal f l u i d s hydrogen ion concentration mucous i n t e r a c t i o n complexing components surface a c t i v i t y bile interaction  Physical p r o p e r t i e s of drug water s o l u b i l i t y lipid solubility partition coefficient  Factors a f f e c t i n g G l t r a n s i t g a s t r i c emptying r a t e food e f f e c t s motility enterohepatic c y c l i n g  Properties of the dosage form d i s i n t e g r a t i o n time d i s s o l u t i o n rate surface area crystal size solvates s a l t form excipients  Factors at absorption s i t e surface area permeability of b a r r i e r s p e c i a l i z e d transport l o c a l blood flow i n t e s t i n a l metabolism Metabolic aspects hepatic metabolism enzyme l e v e l s hepatic p o r t a l blood flow drug binding p r o t e i n s extrahepatic metabolism s a t u r a t i o n phenomena gut wall metabolism Distribution effects plasma p r o t e i n l e v e l s obesity Disease s t a t e s achlorhydria thyrotoxicosis biliary atresia congestive heart  failure  Pharmacological e f f e c t s of drugs m o d i f i c a t i o n of blood flow parasympatholytic a c t i v i t y  pK  Manufacturing v a r i a b l e s granulation process l u b r i c a n t concentration compression pressure t a b l e t coating  11  thus:  AUC  F =  This equation  AUC  Dose  oral  Dose  IV  suggests  IV  oral  t h a t u n e q u a l d o s e s may b e  u s e d t o d e t e r m i n e b i o a v a i l a b i l i t y , however, presupposes that d o s e - l i n e a r k i n e t i c s in  exist.  Therefore,  t h e 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 should  be u s e d .  Independently sampling, the  this  o f t h e AUC d e t e r m i n e d  bioavailabilty  from  plasma  may b e a l s o b e d e t e r m i n e d  t o t a l amount o f d r u g e x c r e t e d  intact  from  i n the urine.  T h i s method r e q u i r e s c o m p l e t e u r i n e c o l l e c t i o n  f o ra  period  10% o f t h e  of at least  dose b e i n g should of  7 h a l f - l i v e s with  excreted  be c a r r i e d  at least  unchanged. G e n e r a l l y ,  out i n conjunction with  t h e b i o a v a i l a b i l i t y from plasma d a t a  independent c o n f i r m a t i o n o f the r e s u l t s  this  assessment  determination  since i t gives obtained  from  plasma. As  stated previously, the l i t e r a t u r e contains  many  examples o f drugs t h a t a r e n o t c o m p l e t e l y b i o a v a i l a b l e (i.e. of  AUC  these  o r a  ^  < AUCjy).  I n many c a s e s ,  drugs i s markedly  administraton.  i n f l u e n c e d by t h e r o u t e o f  I f a d r u g 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 , subcutaneous), artery  the disposition  intravenous,  such t h a t i t d i r e c t l y enters  or vein, distribution  occurs  a  systemic  s o t h a t o n l y -30% o f  the dose o f t h e drug circulation  through  reaches t h e body.  g i v e n by a h e p a t i c r o u t e portal  the l i v e r  on i t s f i r s t  In c o n t r a s t , i f a drug i s  (e.g. p e r os. i n t r a p e r i t o n e a l ,  or splenic vein infusion),  absorption  occurs  a c r o s s t h a t p a r t o f t h e GI e p i t h e l i u m d r a i n e d b y t h e hepatic portal the  entire  mixing  system  absorbed  (Blaschke,  1979).  In these  dose i s exposed t o t h e l i v e r  with the systemic  circulation  a c e r t a i n percentage  be  t o exposure t o t h e r e s t  Thus,  for certain  site  o f t h e dose  will  o f t h e body.  d r u g s 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  d o s e may be m e t a b o l i z e d and  prior to  and, i f h e p a t i c  metabolism occurs, extracted prior  cases,  p r i o r t o the systemic  of pharmacological  action.  circulation  This process i s  known a s h e p a t i c f i r s t - p a s s m e t a b o l i s m o r f i r s t - p a s s effect  ( H a r r i s and Riegelman,  1.3  1969).  Dose-Linearity of Kinetics The  velocity  expressed  of a chemical  reaction  c a n g e n e r a l l y be  by t h e e q u 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 kinetic  r a t e c o n s t a n t and n i s t h e o r d e r o f t h e r e a c t i o n  (Holtzman,  1983).  it  t h a t over  appears  In the pharmacokinetics some f i n i t e  o f most  range n=l thus  drugs  producing  13  an  integrated  should  equation that  i s termed  be n o t e d t h a t t h e use o f t h e term  context  i n pharmacokinetic l i t e r a t u r e .  time course o f drug concentration  processes that  (Holtzman,  1983).  administered clearly  ( Shargel flawed  size  As w e l l , t h e  apparently  first  These " l i n e a r "  order m o d e l s assume  or multiple  doses a r e However, t h i s  view  s i n c e many o f t h e p h a r m a c o k i n e t i c distribution,  biotransformation  e l i m i n a t i o n a r e m e d i a t e d by e n z y m a t i c o r c a r r i e r  systems which c l e a r l y  h a v e some l i m i t a t i o n  capacity.  o f t h e s e systems l e a d s  Saturation  from a p p a r e n t l y of  cannot  term and i s i n s t e a d  and Yu, 1 9 8 5 ) .  processes of absorption, and  buti s  t h e p h a r m a c o k i n e t i c p a r a m e t e r s f o r a d r u g do n o t  c h a n g e when d i f f e r e n t  is  i n this  f o r many d r u g s  e x p r e s s e d by a s i n g l e e x p o n e t i a l  e q u a t e d t o a sum o f s e v e r a l  It  "linear"  i s not t r u l y mathematically rigorous  entrenched  be  "linear".  "nonlinear"  "linear"  o r dose-dependent  In g e n e r a l , display  kinetics  to their to deviation  and, hence, t h e d i s p l a y kinetics.  drugs d i s p l a y i n g dose-dependent  the following characteristics  (Shargel  kinetics  a n d Yu,  1985): 1) Drug e l i m i n a t i o n i s n o t a s i m p l e first-order process. 2)  As dose i n c r e a s e s  so does  elimination  half-life. increase  3) AUC d o e s n o t i n c r e a s e i n dose.  proportionately  t o an  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 b e a f f e c t e d , a t s a t u r a t i o n , b y o t h e r d r u g s r e q u i r i n g t h e same system(s). 5) T h e c o m p o s i t i o n o f m e t a b o l i t e s may b e as t h e dose i s changed.  altered  Since t h e pharmacokinetic parameters as a d d i t i o n a l at  doses  are given, prediction  s t e a d y - s t a t e based  studies  isdifficult.  drug w i l l  display  concentration, kinetics  on d a t a g a t h e r e d Although  "linear"  range  over a s i g n i f i c a n t  from  do d i s p l a y  range.  single  patients  1.4  and e f f i c a c y  on m u l t i p l e d o s e  Effects  dose  t h a t any  linear  I t i s therefore of kinetics of  over t h e u s u a l t h e r a p e u t i c dose range  optimize safety  levels  o v e r an i n f i n i t 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 " a drug  o f drug  i t i s unexpected  kinetics  most d r u g s  may b e a l t e r e d  i n order t o  o f drug treatment t o  therapy.  o f Chronic Renal  F a i l u r e on  Pharmacokinetics  Although of excretion alter  t h e k i d n e y s a r e commonly v i e w e d f o r many d r u g s ,  f a i l u r e can  a l l o f t h e A.D.M.E. p r o c e s s e s , e i t h e r  simultaneously. brought cases,  chronic renal  about  T h e c h a n g e s i n t h e A.D.M.E.  by c h r o n i c r e n a l  the physiological  failure  as organs  singly or processes  reflect,  i n many  r o l e s o f the kidney that are  dissociated this  from simple  organ system t o homeostasis.  1.4.1  Absorption Little  of chronic  lead  and B i o a v a i l a b i l i t y  i n t e n s i v e s t u d y h a s b e e n made on t h e e f f e c t s renal  failure  sequelae of chronic  on d r u g a b s o r p t i o n .  renal  failure  t o changes i n t h e a b s o r p t i o n  pharmaceuticals. the  e x c r e t i o n and t h e importance o f  Features  pancreatitis, 1983) . tract  and c o l i t i s  and t h e r e f o r e  addition,  and b i o a v a i l a b i l i t y o f  a r e common  can a l t e r  diarrhea,  (Hoffsten  and K l a h r ,  the motility  c a n change t h e e x t e n t  of theGl  of absorption  ( R i e g e l m a n a n d Rowland, 1 9 7 3 ) .  the absorption  features of  i n the gastrointestinal  such as nausea, v o m i t i n g ,  These processes  o f many d r u g s  and i t s t h e r a p y c a n  Some o f t h e most p r o n o u n c e d  u r e m i c syndrome a r e d i s p l a y e d  tract.  Y e t many  In  o f many d r u g s i s r e l a t e d t o t h e  degree o f g a s t r i c a c i d i t y .  Patients with  chronic  renal  f a i l u r e may h a v e 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  s w a l l o w i n g o f u r e a and subsequent c o n v e r s i o n  ammonia, o r l o w e r e d due t o a n i n c r e a s e d hydrogen  i o n i n t o t h e stomach.  absorption altered  excretion of  T h u s d r u g s whose  d e p e n d s on t h e pH o f t h e G l t r a c t may h a v e a n  bioavailability  i n patients with  (Anderson and G r a n b e r t o g l i o , could  to  have a s i g n i f i c a n t  mucosa, w h i c h may a f f e c t  1976).  irritant  renal  As w e l l ,  effect  failure ammonia  on t h e G l  both p e r m e a b i l i t y  and t h e  surface  area  absorption  available f o r absorption,  process  t h r o u g h c h a n g e s i n GI  Many p a t i e n t s r o u t i n e l y t a k e  can  and Marbury,  gastric  alteration  emptying  Several uremia e x i s t (1974)  decreased  1974; W e l l i n g ,  been  b y Wood e t a l . (1979) o n t h e b a s i s t h a t t h e groups o f B i a n c h e t t i ' s  were n o t a g e m a t c h e d .  present  shown t h a t a  i n uremic r a t blood  earlier  reports effect  circulating inhibits  pathophysiology  Similarly  extraction  some c r e d e n c e t o the extent of  f o r d - p r o p o x y p h e n e h a s b e e n shown t o b e  i n chronic  summary,  i n man.  study,  T e r a o a n d Shen  o f p r o p r a n o l o l by r a t l i v e r w h i c h l e n d s  alter  et  o f f i r s t - p a s s metabolism f o r  (1985) h a v e s u b s e q u e n t l y  In  effect i n  Both Lowenthal  T h e s e f i n d i n g s h a v e , however,  in particular,  decreased  1984).  first-pass  ( B a l a n t e t a l . , 1983).  and r e n a l f a i l u r e  first-pass  through  a n d B i a n c h e t t i e t a l . (1976) h a v e shown a  challenged  the  antacids  o f g a s t r i c pH, o r a d e l a y i n  (Hurwitz,  extent  fraction  o f d i e t a r y phosphate  o f many d r u g s  r e p o r t s of decreased  propranolol.  control  hydroxide  I t i s w e l l known t h a t  decrease the absorption  complexation,  al.  1984).  motility.  aluminium  t a b l e t s t o decrease the absorption (Lee  and a l s o a l t e r t h e  renal failure  several processes and t h e r a p y  t h e r a t e and e x t e n t  (Gibson  due t o t h e  of chronic  o f drug  e t a l . . 1977).  r e n a l f a i l u r e can  absorption.  1.4.2  D i s t r i b u t i o n and The  volume o f  term which i s the body f l u i d binding,  pH,  Protein  d i s t r i b u t i o n of r e s u l t of  tissue  is a  complex  such p h y s i o l o g i c a l  factors  composition,  membrane p e r m e a b i l i t y ,  capillarisation  (Klotz,  terms, the  volume of  reflection  of  Binding  1976).  a drug  plasma  and  flow  somewhat  d i s t r i b u t i o n i s an  drug-protein binding,  partitioning,  protein  tissue blood In  as  and  simpler  overall  drug-RBC  t i s s u e drug uptake  (Lee  and  Marbury,  1984). Perhaps the the  most n o t a b l e c h a n g e i n d i s t r i b u t i o n i s  a l t e r a t i o n of  drugs.  Several  including  two  Tillement  et  the  extent of protein  notable older a l . . 1978)  patient  with chronic  synthesis, albumin affinity the  protein and  the  presence of  fatty  acids),  possibly site(s)  this  topic  renal  In  et  many  1977;  remained  general,  the  f a i l u r e i s hypoalbuminemic  a l . . 1978).  Furthermore  f o r d r u g s may  be  inhibitors  e t a l . , 1979).  albumin In  due  (e.g. and  binding  contrast,  of  the  altered  presence of metabolic acids,  s t r u c t u r a l changes i n the  due  albumin  t o t a l body d i s t r i b u t i o n  endogenous b i n d i n g  (Tillement  have  r e s t r i c t i o n , decreased  albumin  the  (Reidenberg,  publication.  s h i f t s i n the  (Tillement of  reviews  whose f i n d i n g s  unchanged s i n c e  dietary  of  r e v i e w s h a v e a p p e a r e d on  largely  to  binding  the  to free  concentration  o f the  glycoprotein increased  acute phase r e a c t a n t ,  alpha-l-acid  (AAG, o r o s o m u c o i d ) h a s b e e n shown t o b e  i nhemodialysis patients  (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  associated general is  with renal  failure,  processes t o occur.  generally  cause the  following  The b i n d i n g  of acidic  decreased while that  drugs i s unchanged o r i n c r e a s e d 1984) .  Vd  i = 0.5-0.7 normal  1-1.8 the  of basic  L/kg,  basic  % bound = 7 5 - 8 5  drug d i g o x i n  (  v  %) ( G i b a l d i ,  d n  o  the  r  m  a  i  7.3-8.1  =  in  affinity  o f the  fluids  drug by an organ.  drug  L/kg,  and w i t h % bound  (1984).  The  c h a n g e s on c l e a r a n c e  intrinsic  clearance of  I f unbound d r u g c l e a r a n c e flow,  be s e n s i t i v e t o t h e extent  however, o r g a n c l e a r a n c e  depends  for tissues outside the  and on t h e  comparison t o organ blood  will  1977)  % b o u n d = -17%)  h a s been r e v i e w e d b y Rowland  extracellular 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  influence o f protein binding on  representative  % bound = - 9 0 % ; V d . = uremic  L/kg, '  25 % ; V d _ . = 4 . 4 - 4 . 7 L/kg, uremic (Jusko and Weintraub, 1974).  clearance  or neutral  a c i d i c drug phenytoin  =  The  drugs  (Reidenberg and Drayer,  E x a m p l e s o f b o t h abound w i t h  e x a m p l e s shown b y t h e  and a f f i n i t y ,  i s high  then organ  i s low  clearance  of protein binding. I f , t h e n e l i m i n a t i o n becomes  perfusion  r a t e - l i m i t e d and r e l a t i v e l y  extent of protein  binding.  Chronic renal  failure  s e v e r e anemia which erythropoietin the  r e d blood  into in  i s also  r e s u l t s from  often  accompanied by a  decreased  p r o d u c t i o n and a d e c r e a s e d cell.  erythrocytes  chronic  insensitive t o the  renal  Therefore,  could  life  span o f  drugs which p a r t i t i o n  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  failure.  F o r example, a n e m i c  patients  demonstrate s i g n i f i c a n t l y h i g h e r plasma g e n t a m i c i n than subjects Jackson,  w i t h a normal h a e m a t o c r i t  ( R i f f and  1971).  End-stage renal u p t a k e o f many d r u g s . i s with digoxin decreasing  that  f a i l u r e may a l s o Possibly  clearance,  concentration  failure  1974).  With  i t was n o t e d t h a t t h e  r a t i o decreases.  t h e uptake o f d i g o x i n  decreases as r e n a l  affect the tissue  t h e b e s t example o f t h i s  (Jusko and Weintraub,  creatinine  myocardial/serum implies  levels  This  into the heart  worsens.  Thus, t h e p h y s i o l o g i c a l changes brought about by renal many  failure drugs.  may s u b s t a n t i a l l y a l t e r t h e d i s t r i b u t i o n o f  1.4.3  Metabolism  Although the l i v e r  i s commonly t h o u g h t o f a s t h e  primary metabolic organ f o r drugs, t h e kidney p l a y s significant  role  i n t h e m e t a b o l i s m o f many e n d o g e n o u s  s u b s t a n c e s and x e n o b i o t i c s alteration the  (Gibson,  o f drug metabolism  subject  of several  recent  V e r b e e c k e t a l . . 1981; B a l a n t  Reidenberg  1986).  i n renal reviews  The  failure  has been  ( R e i d e n b e r g , 1977;  e t a l . . 1983; G i b s o n  t i m e , made t h e f o l l o w i n g g e n e r a l i z a t i o n s  respect  t o rates  oxidative  1986).  ( 1 9 7 7 ) , b a s e d on e x a m i n a t i o n s o f s t u d i e s  to that  a)  a  with  o f metabolic drug e l i m i n a t i o n i n uremia:  types o f reactions  normal o r i n c r e a s e d  appeared t o occur a t  r a t e s ; b) r e d u c t i v e  type  reactions  were s l o w e d ; c ) s y n t h e t i c r e a c t i o n s ( e . g . glucuronidation, occurred  sulphation,  a t apparently  normal r a t e s  r e a c t i o n s were slowed.  More r e c e n t  1986), however, s u g g e s t t h a t too of  broad  acetylation)  d) h y d r o l y t i c studies  (Gibson,  t h e s e g e n e r a l i z a t i o n s may be  s i n c e t h e y a r e b a s e d on t o o l i m i t e d  studies.  possibility  a spectrum  V e r b e e c k e t a l . (1981) h i g h l i g h t t h e of  h y d r o l y s i s and r e c i r c u l a t i o n  conjugates, p a r t i c u l a r l y in  glycination,  an a p p a r e n t l y  glucuronides,  prolonged a c t i v i t y  of inactive  w h i c h may  of the parent  result drug.  E x a m p l e s o f t h i s p r o c e s s may o c c u r 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). renal  B a l a n t e t a l . (1983) d e m o n s t r a t e failure  b l o c k e r s and authors,  of a variety  the cephalosporin,  cefoperazone.  Recently, Gibson  drug metabolism,  of renal  t h e work o f R e i d e n b e r g  f i n d i n g s of Gibson previous authors  (1977).  ( R e i d e n b e r g , 1977;  Balant et a l .  alter  h e p a t i c drug metabolism an  f  1983),  important r o l e  Although  failure,  retention  and  inhibiting 1982;  may  metabolism.  t o demonstrate  specific  of drug metabolism i n Massive  n o r m a l l y e x c r e t e d by  The  activity  o x i d a s e system  i n r a t s has been  experimentally  induced renal  Recently,  et a l . .  the kidneys  the conversion of the parent drug  findings  the  the  i n " n e g a t i v e feedback", t h e r e b y  G i b s o n , 1986).  comparable  (2) t h a t  several p o s s i b i l i t i e s exist.  result  approach  (1) r e n a l d i s e a s e  i n xenobiotic  i t is difficult  of metabolites,  k i d n e y , may  Verbeeck  i n that  mechanisms c a u s i n g a l t e r a t i o n s renal  This  and u p d a t e d  I n summary,  on  (1986) c o n c u r w i t h t h o s e o f t h e  1981;  play  of  failure  b o t h h e p a t i c and e x t r a - h e p a t i c .  r e v i e w p r o v i d e s a more c o m p r e h e n s i v e  may  causes of the  (1986) r e v i e w e d many  studies with respect t o the e f f e c t  to  These  i n h e p a t i c metabolism t o the e x i s t e n c e  failure.  of  of beta  however, do n o t r e l a t e any p r e c i s e  alterations renal  on t h e k i n e t i c s  the e f f e c t s  i n man  T e r a o and Shen  (Verbeeck,  o f t h e mixed  function  shown t o be d i m i n i s h e d i n  failure  ( G i b s o n , 1986)  have n o t been  reported.  (1985) d e m o n s t r a t e d  that  a  but  soluble  f r a c t i o n of uremic r a t blood  extraction raising  of propranolol  the  inhibitor. Bianchetti  possibility This  has  an  isolated rat liver,  explain  e t a l . (1976) and  findings  of propranolol  anion transport  1.4.4  (Yates et  Elimination Perhaps the  in  renal  increased  failure  renal  The  clearance  a l l o w s an  of  i s the  are  of the  estimation  cations  D r u g and  diminished  nephron.  derived  not  Metabolites  of the  excretion  and  parent drug by  the  hence  and kidney.  creatinine,  filtration  I t i s recognized,  rate  secretion,  proximal tubule,  (Gibaldi the  particularly in  the  as w e l l  T h e s e p r o c e s s e s may  glomerular  that,  however, t h a t  a c c u r a c y o f k i n e t i c e s t i m a t e s b a s e d on clearance  have  r e f l e c t s drug e l i m i n a t i o n  capable of  segment o f t h e  along the  Intact  of glomerular  P e r r i e r , 1982).  3  liver,  endogenous s u b s t a n c e ,  and  S  failure  i n t o the  normally excreted  a number o f d r u g s ,  i s also  patients.  most o b v i o u s c h a n g e i n p h a r m a c o k i n e t i c s  for  kidney  of  a l . . 1985) .  serum h a l f - l i f e  metabolites that  by  i n uremic  although s i m i l a r r e s u l t s f o r organic been r e p o r t e d  thus  L o w e n t h a l e t a l . (1974)  a l s o been demonstrated t h a t  decreases organic  the  of a c i r c u l a t i n g metabolic  r e s u l t may  decreased clearance It  by  reduced  filtration  as  alter  resorption the  creatinine rate.  Several disease  on  F a b r e and Lee fact  and  a u t h o r s have reviewed the  drug e l i m i n a t i o n Balant,  Marbury,  that  the  1976;  (Dettli,  Jusko,  1984).  1976;  1980;  Their  e f f e c t s of  renal  Levy,  1977;  Vree et a l . .  1983;  approaches stem from  overall elimination  rate  constant  the can  be  E e x p r e s s e d as rate  the  sum  of  renal  non-renal  elimination  constants. K and,  function  K  =  E  of  E  -  < cr>  A  C 1  Thus, drugs can kinetic  classes;a)  routes,  b)  Figure  be  £i  vs  Cl  K  cr  r  e  n  a  j  i  s a  linear  non-renal  = creatinine  b r o k e n up  by  K  then:  clearance,  into three  those eliminated  those eliminated  2:  non-renal  constant  cr  those eliminated  K„  +  A = Cl  A p l o t of  K  creatinine clearance,  where:  c)  +  renal  a s s u m i n g f o r most d r u g s t h a t  K  and  and  s o l e l y by  s o l e l y by both routes  general renal  non-renal (Dettli,  routes, 1976).  f o r e a c h c l a s s o f d r u g s i s shown i n  B  Figure  2: The D e t t l i  Nomogram  (Dettli,  1976) Thus,  i t c a n be seen t h a t t h o s e d r u g s  r e l y i n g on  exclusively  r e n a l mechanisms f o r e l i m i n a t i o n  accumulate,  since their h a l f - l i v e s w i l l  prolonged.  I t a l s o appears  e x c l u s i v e l y by n o n - r e n a l  b e much  t h a t those drugs  routes w i l l  will  have  removed  their  half-lives  substantially unaltered,  however a s p r e v i o u s l y  discussed,  t h i s may b e a n o v e r - s i m p l i f i c a t i o n .  t h e magnitude o f change f o r t h o s e drugs both renal  routes w i l l  well  accumulation failure.  by  elimination.  as accumulation  of the parent  drug,  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  T h i s phenomenon h a s b e e n e x t e n s i v e l y  by V e r b e e c k e t a l . (1981). important  eliminated  d e p e n d on t h e r e l a t i v e m a g n i t u d e s o f  and n o n - r e n a l As  Finally,  since accumulation  Appreciation  reviewed  of this i s  o f m e t a b o l i t e s may l e a d t o  altered impaired  therapeutic or toxic  effects  in a  renally  patient.  I n summary, c h r o n i c r e n a l significant  changes  failure  can produce  i n almost a l l pharmacokinetic  p a r a m e t e r s due t o t h e f a c t t h a t t h e k i d n e y f u l f i l l s other physiological and e l e c t r o l y t e  1.5  r o l e s b e s i d e s maintenance o f f l u i d  balance.  I n f l u e n c e o f H e m o d i a l y s i s on D r u g  D i a l y s i s may b e d e f i n e d crystalline substances their  ( e . g . serum  Removal  as t h e s e p a r a t i o n o f  s u b s t a n c e s (e.g. NaCl)  from  colloidal  albumin) u t i l i z i n g  differences i n  r a t e s o f movement a c r o s s a s e m i - p e r m e a b l e  Hemodialysis  membrane.  involves passing the patients blood through  an " a r t i f i c i a l around which  k i d n e y " w i t h a semi-permeable  flows a d i a l y s a t e  normal plasma.  membrane  of s i m i l a r composition t o  S o l u t e s t h e n a r e f r e e t o move f r o m  to dialysate  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  w a t e r movement  t o removing s o l u t e s removes water  many  (solvent drag).  blood  In addition  from t h e uremic plasma, d i a l y s i s  from t h e d i a l y s i s  also  patient v i a u l t r a -  filtration.  The movement o f a s u b s t a n c e a c r o s s t h e s e m i - p e r m e a b l e membrane i s i n f l u e n c e d b y s e v e r a l  factors  ( G i b s o n and the  Nelson,  1977;  Lee  and  s e m i p e r m e a b l e membrane h a s  s h a p e , m o l e c u l a r s i z e and i n f l u e n c e the easily.  ability  Generally,  Marbury,  d i s c r e t e pores  molecular weight  of the  are water s o l u b l e are  porosity,  and  thickness  of  of the  and  the  are  also significant  solute  proximity  The  h e m o d i a l y s i s has 1977;  Watanabe,  r e m o v a l by  1977;  solute  dialysate  sink  conditions  rate  of  removal of pharmaceuticals  and  many a u t h o r s  G i b s o n and Marbury,  hemodialysis, give  an  several  Nelson,  1984).  removed by  (Gibson  (Lee  and  for passive  Although for  pharmacokinetic  Marbury, gradient  1984).  will  Since  the  i s e s s e n t i a l as  d i f f u s i o n , Vd  importance t o drug d i a l y s a b i l i t y .  et  1977;  i n d i c a t i o n o f whether a drug  of a concentration  force  a l s o be  same r e q u i r e m e n t s a s p l a s m a s o l u t e s  d i a l y s a b l e or not  existence  plasma can  b e e n r e v i e w e d by  Lee  the  parameters can  driving  and  e n t i r e system t o  i n the  Maher, 1977;  g o v e r n e d by  be  blood  rate of  f a c t o r s i n f l u e n c i n g the  solutes  hemodialysis.  al..  of the  The  movement.  Drugs, as by  flow  removed  the  removal.  of  Daltons.  a r e more l i p o p h i l i c .  i n f l u e n c e the  rates  through  generally  s e m i p e r m e a b l e membrane a l s o The  significantly  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  more r e a d i l y t h a n t h o s e t h a t surface' area,  Since  solute  molecule to pass  s o l u t e s w i t h m o l e c u l a r w e i g h t s b e l o w 5000 Substances that  1984).  i s of  Generally,  a  primary drugs  with  Vd  < 1 L/kg  L/kg  w i l l be  w i l l not.  d i a l y s a b l e w h i l e t h o s e w i t h Vd  Furthermore,  s i n c e only f r e e drug  can  removed, d r u g s t h a t a r e h i g h l y p r o t e i n bound a r e likely  t o be  e x c r e t e d p r i m a r i l y by  more d i a l y s a b l e t h a n metabolism.  those p r i m a r i l y  Drugs w i t h v e r y  elimination half-lives maximal d i a l y s e r mL/min, t h o s e  long or very  c l e a r a n c e s a r e on t h e o r d e r o f  s i n c e r e m o v a l by  non-competitive  by  dialysis  the high  contributor to total f o r > 30%  Mathematically, first-order  dialysis  1977,  be  1984). to  Wellhoner  elimination.  Two dialysis 1984;  has  Paton  a  Levy  significant i t must  Several  extended  authors  to describe  Gibson Lee  other  and  and  drug  Nelson,  Marbury,  these  calculations  system.  extensive reviews have a l s o  necessary  G w i l t , 1981;  (1981)  a two-compartment  t o be  t r e a t e d a s any  (Maher, 1977;  Watanabe, 1977;  rendered  body c l e a r a n c e .  may  route of drug  dialysis  not  body c l e a r a n c e o f d r u g  of t o t a l  200  i n t r i n s i c clearance.  have d e s c r i b e d t h e e q u a t i o n s removal by  is  Since  100  clearances >  (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  account  by  are u s u a l l y not d i a l y s a b l e .  drugs with metabolic  be  short  (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  dialysable  Those  the kidney w i l l excreted  be  not  e x t e n s i v e l y removed b y h e m o d i a l y s i s .  drugs normally  mL/min  > 2  recently  e t a l . . 1985).  of drug  r e m o v a l by  appeared  (Janknegt  peritoneal and  Koks,  1.6  Metoclopramide Pharmacokinetics  1.6.1  Animal  Models  Animal experiments t h a t metoclopramide metabolized, (Tunon al.  and r a p i d l y  et al..  r a t , a n d dog) h a v e shown  (MCP) i s w e l l excreted  absorbed,  extensively  i n the species  1974; Bakke a n d S e g u r a ,  1980; Tarn e t a l . .  r  (rabbit,  studied  1976; Bateman e t  1981). M e t a b o l i s m 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 t h e N [rabb'it, dog] ( A r i t a Bateman e t a l . . and  e t a l . . 1970 ; Cowan e t a l . . 1976;  1978),  amide h y d r o l y s i s  1970;  o r a l MCP d o s i n g .  1976)  gave  Early reports  et a l . .  1976).  (Bakke  and Segura,  o f MCP f o l l o w i n g I V i n the rat, rabbit,  Somewhat i n c o n t r a s t t o t h i s ,  (1978) d e m o n s t r a t e d  t h e r a t w i t h dose-dependent  a b o v e 15 mg/kg. et  1976; Cowan e t a l . ,  a s 20, 28, a n d 3 6 m i n u t e s  and d o g r e s p e c t i v e l y .  in  dog] ( A r i t a  the elimination h a l f - l i f e  and A x e l s o n  N-de-ethylation  c o n c e n t r a t i o n s o c c u r 30-120 m i n u t e s  after  injection  O-demethylation,  [rat, r a b b i t ,  Bakke a n d S e g u r a , Peak p l a s m a  position  a half-life changes  Furthermore s t u d i e s  in  o f 50 m i n u t e s  ^2./2  saturable  f i r s t - p a s s metabolism  1 mg/kg a n d u n u s u a l d o s e - d e p e n d e n t a p p a r e n t l y MCP  d  s  e  s  MCP  a t doses  below  k i n e t i c s due t o  induced h e p a t i c b l o o d f l o w changes a t  d o s e s a b o v e 15 mg/kg.  o  i n t h e r a t by K a p i l  a l . (1984) a n d Tarn e t a l . (1981) s u g g e s t t h a t  undergoes  Tarn  Tam  e t a l . (1981a) h a v e a l s o c a r r i e d  studies  i n rats with  hepatic  failure.  failure  l e a d s t o an  half-life curve  and  (AUC).  experimentally induced  Experimentally  the  Volume o f d i s t r i b u t i o n ,  formation  approximately  least with  ureteral  a two-fold  (5/6  the  ligation,  these  time  shown  animals  metabolite  with  was  of  this  experimentally  nephrectomy,  or uranyl nitrate)  in total  slightly  yet  body  showed  and  at  AUC  clearance.  decreased  in  these  investigators postulated  e x t r a h e p a t i c m e t a b o l i s m as t h e mechanism f o r  o u t by  seen i n r e n a l f a i l u r e ,  Kapil  e t a l . (1984).  mechanism i s t h e d e c r e a s e to renal failure 1984)  i n these  i n c r e a s e i n plasma h a l f - l i f e  Although  alterations  ruled  doubled  two-step  V o l u m e o f d i s t r i b u t i o n was  diminished  hepatic  i n c r e a s e i n plasma  extrahepatic formation  a p r o p o r t i o n a l decrease  animals.  (CCl^)  and  h o w e v e r , was  I n v e s t i g a t i o n s of animals  renal failure  bilateral  renal  Urinary e x c r e t i o n of  of the N-de-ethylated  unchanged, s u g g e s t i n g  induced  kinetic  area under the plasma c o n c e n t r a t i o n vs  was  substance.  induced  approximate 3 f o l d  t o remain e s s e n t i a l l y unchanged. i n t a c t MCP  out  t h i s has  A more  likely  i n h e p a t i c metabolism  (Bateman e t a l . . 1981;  been  Kapil  secondary  et a l . .  Human S t u d i e s  1.6.2 Several  s t u d i e s h a v e b e e n c o m p l e t e d on t h e  p h a 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 healthy volunteers. focus e i t h e r  The k i n e t i c  Bryson e t a l . ,  infusion)  1985; S a i l e r  doses  (5-50 mg)  1979;  Bateman e t a l .  Bateman e t a l . .  f  et al.,  studies  m e t h o d o l o g i c a l problems t h a t findings.  three general selectivity  Basically  catagories:  (Schuppan  al.,  IV doses  1979;  (Schuppan  failure  sensitive  fall  1979; Bateman e t a l . ,  assessments  into  1980)  reference  (Schuppan e t  1979; Bateman e t a l . . 1980;  1981) (3) f a i l u r e  Block e t a l . .  The be  et al.,  and/or  sensitivity/  o r capsule as t h e o r a l  f  many o f t h e  some d e g r e e o f d o u b t on  (1) p o o r a s s a y  1979; G r a f f n e r e t a l .  1983).  studies  from a n a l y t i c a l  these d e f i c i e n c i e s  form i n b i o a v a i l a b i l i t y  Ross-Lee and  cast  et al..  (2) t h e u s e o f a t a b l e t dosage  1981; Bateman,  unfortunately,  suffer  et a l . .  e t a l . , 1981;  " h i g h - d o s e " chemotherapy done,  1984;  1979; S c h u p p a n  1981; B l o c k e t a l . .  "low-dose"  chemotherapy  1985) o r on l o w e r  1980; R o s s - L e e  have been g e n e r a l l y w e l l  tended t o  (Taylor e t a l . ,  (Graffner e t a l . ,  W h i l e t h e more r e c e n t  their  s t u d i e s have  on t h e d o s e s u s e d i n c a n c e r  (1-2 mg/kg a s a s h o r t  existing  o f MCP i n n o r m a l ,  et al..  t o compare e q u a l  oral  1979; G r a f f n e r e t a l . ,  1981).  o f many o f t h e p r e v i o u s a s s a y methods t o  and s e l e c t i v e has r e s u l t e d  i n several  problems.  The most s i g n i f i c a n t  of these i s the lack  ability  t o sample plasma  produce  an a c c u r a t e e s t i m a t e o f t h e t r u e  half-life. truncation  Gibaldi  l o n g enough a f t e r d o s i n g t o  and W e i n t r a u b  of the sampling i n t e r v a l  of  in half-life  dose-dependency  Bateman, 1983)  The dosage  use  form  of a t a b l e t  dissolution  be  an  The  l e d to claims  (Bateman e t a l . ,  o r c a p s u l e as t h e o r a l s t u d i e s can  1980;  reference  be  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  r a t e s can s u b s t a n t i a l l y  Although  alter  oral  and  IV d o s e s ,  dosage  solution.  i t i s p o s s i b l e t o determine oral  and  bioavailabiltiy  A more a p p r o p r i a t e  i s the commercially a v a i l a b l e  from unequal  that  artifactual.  ( R i e g e l m a n and Rowland, 1 9 7 3 ) . form  half-life.  kinetics  in bioavailability  inappropriate  can l e a d t o  d e t e r m i n a t i o n has  o f MCP  w h i c h may  biological  (1971) h a v e shown  underestimation of the b i o l o g i c a l inaccuracy  of  bioavailabiltiy  such a d e t e r m i n a t i o n i s  based  on t h e 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  range  i n question.  P r i o r t o 1984,  no  over the  dose  such d e t e r m i n a t i o n  h a d b e e n made, i n f a c t t h e e v i d e n c e f r o m a n i m a l m o d e l s (Kapil  et a l . ,  contrary.  1984;  Tam  et a l . ,  Recently, Wright  demonstrated  1981)  was  quite to the  e t a l . (1984) h a v e  linear kinetics  i n the range  o f 20  L i n e a r k i n e t i c s have a l s o been o b s e r v e d i n t h e c a n c e r chemotherapy  trials  (Bryson e t a l . .  - 100  mg.  high-dose  1985).  These  d o s a g e s a r e , however, c o v e r examined i n t h e  following  I n g e n e r a l , MCP the  Gl with  al..  1979;  widely  MCP  f r o m 2.2  i s -40  - 3.4  those  first-pass  effect MCP  be  distribution  ( H a r r i n g t o n e t a l . . 1983).  I n man,  MCP  4 to the N -sulphonate  metabolized  from  (Bateman e t  appears to  w i t h volume o f  L/kg  absorbed  % bound t o plasma p r o t e i n s p a r t i c u l a r l y  (Webb e t a l . . 1 9 8 6 ) .  dose)  rapidly  Ross-Lee e t a l . . 1981). i n man  range from  study.  a p p e a r s t o be  a significant  distributed  ranging  a different  (Bateman e t a l . , 1980;  is  to  AAG  predominantly  (-32-40% o f IV o r  T e n g e t a l . . 1977)  oral  as  well  4 as  a minor  (<5%)  Approximately  c o n t r i b u t i o n from the N  25  % o f t h e dose i s e x c r e t e d  (Teng e t a l . , 1 9 7 7 ) . high  (11.61 mL/min/kg)  renal  clearance  T o t a l body c l e a r a n c e  a b o u t MCP that  the  and  claims  s h o u l d be  renal failure.  showed a h i g h e r  is  relatively  value.  hours dependency  Bateman,  i t was  1983).  significantly  unexpected  altered  in  However, s e v e r a l r e p o r t s  incidence of side e f f e c t s  u r e m i c p a t i e n t s g i v e n MCP  with  % of t h i s  of dose  drug  information available  i n n o r m a l human v o l u n t e e r s kinetics  intact  - 5.1  ( G r a f f n e r e t a l . . 1979;  the pharmacokinetic  patients with Lancet  f o r a b o u t 20  r a n g e s f r o m 2.6  ( H a r r i n g t o n e t a l . , 1983)  Given  as  ( H a r r i n g t o n e t a l . . 1983)  accounting  Elimination h a l f - l i f e  h a v e b e e n made  -glucuronide.  (Caralps,  1979;  in  to  Bateman and was  1979;  Bateman and  body c l e a r a n c e  a l . . 1981).  1985)  o f MCP  i n uremic  Recently another  has been completed  total  body c l e a r a n c e  suggests that hemodialysis  1986) This  and  i s probably the r e s u l t  distribution responsible  o f MCP.  not been  patients.  failure.  decrease  MCP  evidence Lehmann  (Berardi et a l . . from t h e  body.  o f t h e l a r g e volume  of  mechanism h a s b e e n p r o v e n c h a n g e s i n MCP  to  be  kinetics  Lehmann e t a l . (1986) h a v e  a c i r c u l a t i n g metabolic i n h i b i t o r but t h i s substantiated.  in  in  (Bateman e t a l . . 1981,  f o r the unexpected  shown b y u r e m i c suggested  No  (Bateman  increase  Preliminary  a t removing  in  (Lehmann e t a l . .  a two-fold  peritoneal dialysis  are i n e f f e c t i v e  patients  study  This  large decrease  with a proportional  plasma e l i m i n a t i o n h a l f - l i f e .  a l . 1985)  1980).  i n patients with renal  T h e s e s t u d i e s h a v e shown a t l e a s t  et  Gokal,  l a t e r a t t r i b u t e d t o an u n e x p e c t e d l y  total et  Davies,  has  2. 2.1  M a t e r i a l s and  2.1.1  Chemicals  The  EXPERIMENTAL  Supplies  f o l l o w i n g were s u p p l i e d by A.H.  Robins  Canada  I n c . , M o n t r e a l , Quebec: 4-amino-5-chloro-2-methoxy-N-(2-diethyl  aminoethyl)  benzamide monohydrochloride  (MCP.HC1.H 0)  ( L o t Nos.  A105  Injectable,  and  2 mL  F 0 5 8 ) , MCP.HCl  Ampule)  lmg/mL ( R e g l a n , 100 mL R  H 0 2  Tablets  10 mg  Maprotaline.HCl  monohydrate  ( L o t No. bottle)  (Reglan )  (MAP  HCl)  Mississauga, 2.1.2  ( L o t No.  MCP.HCl 8474),  Syrup  MCP.HCl  84707).  propanamide H y d r o c h l o r i d e )  s u p p l i e d by C i b a P h a r m a c e u t i c a l s ,  Ontario.  Reagents ACS  reagent grade  Sodium H y d r o x i d e p e l l e t s  obtained  from F i s h e r S c i e n t i f i c  U.S.A..  ACS  obtained  from  WA,  84637),  R  (N-methyl  -9-10-ethanoanthracene-9(10H) L o t A11663096472-0 was  5 mg/mL ( R e g l a n  ( L o t No.  R  2  U.S.A..  Co.,  Fair  Lawn  reagent grade H y d r o c h l o r i c A c i d American  Scientific  , NJ,  37%  and C h e m i c a l ,  Ammonia S o l u t i o n S t r o n g 27% was  from M a l l i n c k r o d t  were  I n c . , S t . L o u i s , MI,  was Seattle,  obtained  U.S.A..  H e p t a f l u o r o b u t y r i c Anhydride S e q u a n a l G r a d e were o b t a i n e d Rockford,  I L , U.S.A..  2.1.3  Solvents Benzene and t o l u e n e  obtained Ont..  from Caledon  and T r i e t h y l a m i n e  from P i e r c e Chemical  (distilled  i n glass)  System, M i l l i p o r e  M e t h a n o l ACS r e a g e n t were o b t a i n e d  2.1.4  were  L a b o r a t o r i e s I n c . , Georgetown,  D e i o n i z e d w a t e r was p r o d u c e d on s i t e  Milli-RO  Co.,  via a  Corp., Bedford,  grade and acetone  f r o m BDH C h e m i c a l s ,  MA.,  U.S.A..  ACS r e a g e n t  Toronto,  grade  Ontario.  Gases N i t r o g e n U.S.P.and  Union Carbide  2.1.5  (95:5) were o b t a i n e d  S u p p l i e s f o r Human drug  Argyle  R  Republic  a  TM Venocut  infusion  INT c a n n u l a  blood  s e t (19 g a u g e  needle)  S t . L o u i s , MI, U.S.A..  (Abbott  o f I r e l a n d ) was i m p l a n t e d  arm t o f a c i l i t a t e plastic  from Matheson  Experiments  f r o m Sherwood M e d i c a l ,  Butterfly -19  Hydrogen  a d m i n i s t r a t i o n was made t h r o u g h  R  obtained  Ontario.  from  Canada L t d ; Edmonton, A l b e r t a .  Intravenous  sterile  A i r were o b t a i n e d  Canada L t d . , T o r o n t o ,  UHP a n d A r g o n / M e t h a n e Gas P r o d u c t s  Medical  sampling.  Ireland,  A  Sligo,  i n the contralateral Glass  1 mL  (Glaspak ),  1 mL a n d 3 mL s y r i n g e s , 22 a n d 25 g a u g e  needles,  a n d l u e r a d a p t e r s were o b t a i n e d Canada, M i s s i s s a u g a , collected B.C.).  Ontario.  i n Whirl-pak  bags  from B e c t o n - D i c k s o n U r i n e s a m p l e s were  (AHS Canada,  Whole b l o o d was c o l l e c t e d  into  Richmond,  heparinized  v a c u t a i n e r t u b e s ( V a c u t a i n e r S y s t e m s , R u t h e r f o r d , NJ, U.S.A.). frozen  F o l l o w i n g c e n t r i f u g a t i o n t h e p l a s m a was  in sterile  Corning,  NY,  2.2  Pyrex  stored  t u b e s ( C o r n i n g G l a s s Works,  U.S.A.).  Equipment A model  584OA H e w l e t t - P a c k a r d g a s c h r o m a t o g r a p h 63  equipped with a model  N i electron capture detector  18850A GC t e r m i n a l  c o l u m n c o m p a t i b l e model  and i n t e g r a t o r , 18835B c a p i l l a r y  (ECD), a  and a packed inlet  system,  H e w l e t t P a c k a r d Co., A v o n d a l e , PA, U.S.A.; a b o n d e d fused  silica  capillary  column  (5% phenyl methyl  s t a t i o n a r y phase, c r o s s - l i n k e d ; phase r a t i o  film  thickness  150, c o l u m n I.D. 0.31 mm,  phase  silicone 0.52 um,  c o l u m n l e n g t h 25m),  H e w l e t t - P a c k a r d Co., P a l o A l t o , CA, U.S.A.; v o r t e x - t y p e R R m i x e r ( V o r t e x - G e n i e ) , i n c u b a t i o n oven (Isotemp , model 350),  F i s h e r Accumet  pH m e t e r M o d e l  with temperature c o n t r o l , Scientific  Industries,  2K C e n t r i f u g e ,  (Haake DI m o d e l ) ,  Springfield,  Damon/IEC d i v i s i o n ,  U.S.A.; r o t a t i n g - t y p e t u b e m i x e r 415-110),  Labindustries,  62 0, w a t e r b a t h Fisher  I L , U.S.A.; I E C M o d e l Needham H t s . , MA,  (Labquake , model  Berkeley,  CA, U.S.A.; 15 mL  Pyrex  c u l t u r e tubes with  Teflon  lined  screw  caps,  C a n l a b , V a n c o u v e r , B.C. 2.3  Preparation  2.3.1  Metoclopramide.HCl Approximately  ~10  of solutions  11.81 mg o f MCP.HC1.H 0 2  mg o f MCP f r e e b a s e ) was a c c u r a t e l y  transferred deionized  t o a 100 mL v o l u m e t r i c  w a t e r . A volume,  t o 100 mL i n a v o l u m e t r i c  water.  The f i n a l  this  s o l u t i o n was deionionized  s o l u t i o n was p r o d u c e d b y  of the f i n a l  with  deionized  working stock  water.  s o l u t i o n was  ug/mL.  2.3.2  Maprotaline Approximately  mg o f MAP  deionized mL w i t h  (MAP).HCL  11.31 mg o f MAP H C l ( e q u i v a l e n t  t o -10  f r e e b a s e ) was a c c u r a t e l y w e i g h e d a n d  transferred  50  working stock  flask with  i n a 50 mL v o l u m e t r i c  concentration  -0.04  f l a s k and d i s s o l v e d i n  a 10 mL a l i q u o t o f t h e s e c o n d s o l u t i o n a n d  diluting The  weighed,  (0.2 mL), o f t h i s  diluted  taking  (equivalent t o  t o a 100 mL v o l u m e t r i c  water.  A volume,  deionized  concentration  f l a s k and d i s s o l v e d i n  0.2 mL, was t h e n d i l u t e d t o  water i n a v o l u m e t r i c  flask.  The  o f t h i s w o r k i n g 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  mL  ACS  with  reagent  grade concentrated  (37%)  to  100  8.3 mL  Sodium H y d r o x i d e  5 N s o l u t i o n s were  by  (NaOH) 1 N and  dissolving  4 and  20  g,  i n d e i o n i z e d w a t e r i n 100  Ammonium H y d r o x i d e 4% of Strong  was  Ammonia s o l u t i o n  Triethylamine, prepared  by  diluting  toluene  pellets  0.0125 M 0.125  (30%)  mL  Sample E x t r a c t i o n  2.4.1  Biological The  method u s e d  0.1  u r i n e , • c o n t a i n i n g MCP c l e a n Pyrex internal  R  (0.4  by  t o 100  flasks.  diluting mL  13.3  with  flask. solution  was  flask.  mL  F o u r o r f i v e NaOH  solution.  procedure  Fluid Extraction i s identical  e t a l . (1983) and  o r uremic plasma,  volumetric  o f NaOH  t r i e t h y l a m i n e t o 100  added t o t h e  2.4  mL  i n toluene,  i n a volumetric  were t h e n  respectively,  prepared  d e i o n i z e d water i n a v o l u m e t r i c  Riggs  diluting  flask.  pellets  with  HCl  by  d e i o n i z e d water i n a v o l u m e t r i c  prepared  mL  prepared  t o t h a t developed  i s o u t l i n e d i n Scheme 1.  - 0.5  mL,  o r 0.01  following dosing,  t u b e c o n t a i n i n g 0.50 ug/mL) s t a n d a r d  mL  t o 0.10  Normal mL  of  were a d d e d t o  1 N NaOH, 0.2  solution.  by  The  tubes  mL  a MAP  were  t h e n made up t o a v o l u m e o f 2.2 mL w i t h d i s t i l l e d F o l l o w i n g t h e a d d i t i o n o f 6 mL b e n z e n e t h e t u b e s  water. were  capped, w i t h T e f l o n - l i n e d  caps,  m i n u t e s on a r o t a t i n g  (Labquake ) t o e x t r a c t t h e  rack  m e t o c l o p r a m i d e and m a p r o t a l i n e . 2300 g f o r 2 X 5 and  a n d r o t a t e d f o r 20  After centrifugation at  m i n u t e s t h e o r g a n i c p h a s e was removed  b a c k - e x t r a c t e d u s i n g 2 mL o f 1 N H C l t h e n  2 0 m i n u t e s on a r o t a t i n g  rack.  Following  rotatedf o r  centrifugation  for  5 minutes  (@ 2300 g) t h e o r g a n i c l a y e r was a s p i r a t e d  and  discarded  ( w a t e r vacuum a s p i r a t o r ) .  The r e m a i n i n g  a q u e o u s l a y e r was washed t w i c e w i t h  4 mL o f b e n z e n e ,  w h i c h were s u b s e q u e n t l y  The r e m a i n i n g  l a y e r was a l k a l i n i z e d  aspirated.  with  aqueous  0.5 mL 5 N NaOH a n d t h e n  extracted  f o r 20 m i n u t e s f o l l o w i n g t h e a d d i t i o n  benzene.  Following centrifugation  o f 6 mL  (5 m i n @ 2300 g ) , 5 mL  o f t h e o r g a n i c l a y e r was removed a n d d r i e d u n d e r a g e n t l e flow o f n i t r o g e n i n a 40  °C w a t e r b a t h .  derivatized 2.4.2  r e s i d u e s were  Formation  nitrogen dried  r e s i d u e was r e c o n s t i t u t e d  u L o f 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 .  reconstitution  with  Following  2 0 uL o f h e p t a f l u o r o b u t y r i c anhydride  added and t h e samples b r i e f l y mixing.  then  a s f o l l o w s p r i o r t o GC-ECD a n a l y s i s .  Derivative The  800  The n i t r o g e n d r i e d  T h e s a m p l e s were t h e n  vortexed  t o ensure  were  complete  i n c u b a t e d 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 solutions.  P l a s m a s a m p l e s (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 , b e n z e n e , m i x , 20 m i n c e n t r i f u g e , 10 m i n  6 mL  discard aqueous l a y e r Organic  layer 2 mL IN H C l , m i x , 20. m i n c e n t r i f u g e , 5 min  discard organic layer wash t w i c e w i t h 4 mL b e n z e n e Aqueous  .ayer 0.5 mL 5N NaOH, 6 mL b e n z e n e mix, 20 m i n c e n t r i f u g e , 5 min  discard aqueous l a y e r Organic  layer  evaporate t o dryness u n d e r 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 u L 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 t e m p e r a t u r e . 0.5 mL H2O, v o r t e x , 10 s e c . 0.5 mL NH4OH, v o r t e x , 10 s e c . c e n t r i f u g e , 1 min. Transfer organic layer t o v i a l s  Inject Scheme 1: E x t r a c t i o n  i n t o GC  Procedure  (2 u L )  ( R i g g s e t a l . . 1983)  1 hour. cool  Following  i n c u b a t i o n t h e t u b e s were a l l o w e d t o  t o room t e m p e r a t u r e ,  a t which  t i m e t h e e x c e s s HFBA  r e a g e n t was h y d r o l y z e d b y t h e a d d i t i o n distilled  water  and v o r t e x i n g  o f 0.5 mL  f o r 10 s e c o n d s .  a c i d was t h e n n e u t r a l i z e d b y t h e a d d i t i o n NH OH a n d v o r t e x i n g 4  centrifugation  f o r 10 s e c o n d s  l a y e r was t h e n i m m e d i a t e l y t r a n s f e r r e d  GC-ECD  from which  o f 0.5 mL 4%  f o l l o w e d by  (@ 2300 g) f o r 1 m i n u t e .  autosampler v i a l s  The e x c e s s  The o r g a n i c to clean  2 u L were i n j e c t e d f o r  analysis.  2.5  Standard Curve Capillary  Preparation  f o r Fused  Silica  GC-ECD A n a l y s i s .  V o l u m e s o f 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 c l e a n Pyrex  tubes containing  0.2 mL MAP.HCl NaOH.  stock solution  0.2 mL b l a n k human  into plasma,  (0.4 ug/mL), a n d 0.5 mL 1 N  E a c h t u b e was t h e n made up t o a v o l u m e o f 2.2 mL  with d i s t i l l e d Sections  water  Capillary  2.6.1  GC-ECD The  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  2.4.1 a n d 2.4.2.  2.6  GC-ECD  Parameters  parameters  f o r t h e GC-ECD s y s t e m  I n j e c t i o n temperature 205  (0.04 ug/mL) were p i p e t t e d  °C; d e t e c t o r  2 60  °C; i n i t i a l  (ECD) t e m p e r a t u r e  a r e as f o l l o w s :  column  temperature  350 °C; c a r r i e r g a s  (Hydrogen) f l o w  30  mL/min; c a r r i e r  95:5)  60  mL/min; i n l e t  flow  rate  attenuation  2 ;  0.15  - 0.4;  valve  1.75  min.;  0.81  minutes.  2.6.2  6  chart  s p e e d 0.4  open t i m e 0.1  r a t e of temperature  (Argon-Methane  pressure  applicability  of the  min,  valve  increase  However, t h e  ability  presence of the  fluid,  of the  p.s.i.;  4  sensitivity  closed  time  °C/min  after  Plasma  a s s a y method had  b e e n shown t o human p l a s m a and sheep plasma, a m n i o t i c  10  cm/min; s l o p e  A p p l i c a t i o n of Assay t o Uremic  The  A  gas  urine  previously  samples,  tracheal  fluid  as w e l l and  assay to q u a n t i f y  urine.  MCP  components o f u r e m i c serum was  and  a l i q u o t s of  uL  and  d e r i v a t i z e d as  were e x t r a c t e d  2.4.1  and  2.4.2  150,  200,  250,  q u a n t i t a t i o n o f e i t h e r MCP  2.7  or  Pharmacokinetic Studies  sections  detection  MAP.  i n N o r m a l and  Uremic  Humans. 2.7.1  Experimental Protocol  i n Normal,  Healthy  Volunteers S i x male, non-smoking v o l u n t e e r s written  consent p r i o r t o the  500  component o f  b l a n k uremic plasma would i n t e r f e r e w i t h the and  the  several and  outlined in  t o d e t e r m i n e w h e t h e r any  in  unknown.  s e r i e s o f b l a n k p l a s m a s a m p l e s were drawn f r o m  uremic volunteers  as  gave  initiation  informed,  of the  study.  the  All  v o l u n t e e r s were h e a l t h y a s a s s e s s e d b y a p h y s i c a l  examination  and by 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  laboratory tests. prior  history  More s p e c i f i c a l l y  o f , any a b n o r m a l i t y  none showed, o r h a d  of hepatic  function,  ( a s d e m o n s t r a t e d b y SGOT, SGPT, o r ALK PHOS measurements), o r r e n a l serum c r e a t i n i n e ,  and c r e a t i n i n e  s u b j e c t s were f a s t e d  study  The basis.  f o r one week p r i o r t o t h e  r e q u i r e d t o a b s t a i n from  alcohol for  t o and d u r i n g t h e s t u d y .  s t u d y was c o n d u c t e d  on a f o u r - w a y  a 5 a n d 20 mg d o s e o f MCP , A.H. R o b i n s ) .  d o s e o f MCP  oral  i n oral  crossover IV dose  (Reglan  , A.H.  solution while the other  Robins).  s e p a r a t e d by a t l e a s t washout.  On a s t u d y  (Butterfly-19  facilitate  d o s e a s an o r a l  A l l drug  blood  form  received a three tablet  a d m i n i s t r a t i o n s were  one week t o a l l o w f o r c o m p l e t e  drug  d a y , an i n d w e l l i n g c a n n u l a  INT, V e n i s y s t e m s ,  i n a forearm  solution  Three v o l u n t e e r s then  v o l u n t e e r s r e c e i v e d a 10 mg MCP  placed  including  I n j e c t a b l e , A.H. R o b i n s Canada I n c . , M o n t r e a l ,  (Reglan 10 mg  A l lvolunteers  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  (Reglan Que),  administration.  medications,  a n d were a l s o  48 h o u r s p r i o r  clearance). A l l  t o avoid other medications,  over-the-counter  BUN,  f o r 12 h o u r s p r i o r t o d o s i n g a n d f o r  4 hours f o l l o w i n g drug were i n s t r u c t e d  f u n c t i o n (as d e m o n s t r a t e d by  vein prior  sampling,  Abbott  t o drug  I r e l a n d L t d . ) was administration to  a b l a n k b l o o d sample t a k e n  and  the patency experiment  of the cannula maintained throughout the using heparinized saline  (50 U/mL).  On t h e d a y o f t h e I V a d m i n i s t r a t i o n , was i m p l a n t e d sampling short 944  i n the forearm c o n t r a l a t e r a l  cannula.  IV i n f u s i o n  i n f u s i o n pump  another  cannula  to the  T h e 10 mg MCP d o s e was t h e n g i v e n a s a o v e r 3.5 m i n u t e s (Millis,  MA).  using a Harvard  Oral drug  was a c c o m p a n i e d b y ~200 mL o f w a t e r .  Model  administration  B l o o d s a m p l e s (5  mL) w e r e t a k e n a t -5, 2, 4, 6, 10, 20, 40, a n d 60 minutes, and  72 h o u r s  oral at 10,  a n d 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 24, 48,  drug  following  IV drug  administration,  administration.  b l o o d samples  15, 30, 45, and 60 m i n u t e s ,  saline,  into  lithium  heparin  a f t e r removal  B l o o d was drawn  of the heparinized  10 mL g l a s s V a c u t a i n e r t u b e s c o n t a i n i n g ( 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.). centrifugation, screw-on T e f l o n  T h e p l a s m a was s e p a r a t e d b y  placed i n fresh glass lined  caps,  On a l l o c c a s i o n s , a t o t a l  urine collection  f o r the f i r s t  U r i n e was c a r e f u l l y  gathered  analysis.  with  analysis.  f o r 72 h o u r s ,  12 h o u r s , was made.  i n p l a s t i c Whirl-pak  t h e v o l u m e a n d pH i m m e d i a t e l y frozen u n t i l  (Pyrex ) tubes  and f r o z e n u n t i l  at hourly intervals  stored,  (5 mL) were drawn  a n d 1.5, 2, 3, 5, 6, 8,  12, 14, 16, 24, 48, a n d 72 h o u r s .  from t h e c a n n u l a ,  Following  bags,  measured, and an a l i q u o t  6 Normal, healthy volunteers well matched for age, height, and weight  -Fasted 12 h prior to and for the f i r s t 4h post-dose -No medications for 1 week prior to or during study -No alcohol 48 h prior to or during study  n=6  n=6  5 mg MCP oral solution  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: S t u d y P r o t o c o l i n Normal H e a l t h y 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 P l a s m a s a m p l e s 0.2-0.5 mL were e x t r a c t e d a n d  derivatized  a s d e s c r i b e d i n S e c t i o n s 2.4.1 a n d 2.4.2.  M a p r o t a l i n e H C l (0.4 ug/mL) was u s e d standard.  as t h e i n t e r n a l  E a c h s a m p l e was m e a s u r e d i n d u p l i c a t e .  d u p l i c a t e was i n j e c t e d  (2 u L ) t w i c e  Each  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 b y f i t t i n g t h e area-ratios standard  o f t h e HFB d e r i v a t i v e s o f MCP/MAP t o t h e  curve  regression line  concentration). derivatized, volunteer  Standard  ( a r e a r a t i o MCP/MAP v s MCP  curve  s a m p l e s were e x t r a c t e d ,  a n d c h r o m a t o g r a p h e d o n t h e same d a y a s t h e  samples.  The s t u d y  i n normals i s summarized i n  Scheme 2.  2.7.3  Experimental Eight patients,  renal on  impairment  P r o t o c o l f o r Uremic  Volunteers  7 male and 1 female,  with  ( c r e a t i n i n e c l e a r a n c e < 10 mL/min) a n d  m a i n t e n a n c e h e m o d i a l y s i s were s t u d i e d .  approval  Following  o f t h e s t u d y p r o t o c o l b y t h e Human E t h i c s  Committee o f t h e U n i v e r s i t y p a t i e n t s gave informed,  of British  Columbia, a l l  w r i t t e n consent.  Values  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 , part  of the routine c l i n i c a l  patients,  severe  monitoring  for  taken as  o f these  were r e c o r d e d p r i o r t o d r u g a d m i n i s t r a t i o n .  All  patients  fasted  administration  f o r 12 h o u r s p r i o r t o d r u g  and f o r a t l e a s t  administration.  The u r e m i c  medications required no  1 hour a f t e r  drug  s u b j e c t s c o n t i n u e d any  f o rtherapy  (see Appendix),  i n t e r f e r e n c e was n o t e d i n t h e m e t o c l o p r a m i d e  however, assay  from any o f t h e s e s u b s t a n c e s .  The  uremic p a t i e n t s r e c e i v e d  on two s e p a r a t e o c c a s i o n s . occurred  24 h o u r s p r i o r  was g i v e n b y a s h o r t 944  a 10 mg I V d o s e  The f i r s t  drug  to a dialysis  IV i n f u s i o n ,  administration  session.  The dose  u s i n g a Harvard Model  i n f u s i o n pump, o v e r 3.5 m i n u t e s .  mL, were t a k e n f r o m an i n d w e l l i n g  o f MCP  B l o o d samples,  1  cannula  (Butterfly-19-INT , Venisystems, Abbott I r e l a n d Ltd.) R  into  a glass  1 mL t u b e r c u l i n  syringe  (Glaspak, Becton and  D i c k s o n , R u t h e r f o r d N J , U.S.A,) a n d p r o c e s s e d a s o u t l i n e d f o r t h e normal samples and  v o l u n t e e r s (see S e c t i o n  1.5, 2, 3, 4, 6, 8, 10, 12, a n d 24 h o u r s  dialyser  arterial  hemodialysis.  and a t h a l f - h o u r l y  and venous l i n e s  Following a period  t o a l l o w f o r complete were g i v e n a s e c o n d dialysis.  following  intervals  10 mg I V d o s e  of at least  one week, patients  1 hour p r i o r t o  were t a k e n a t -15, 5, 15, 30,  then h a l f - h o u r l y  and venous l i n e s  from t h e  f o rthe duration of  d r u g washout, t h e u r e m i c  B l o o d samples  a n d 60 m i n u t e s ,  arterial  Blood  were drawn a t -15, 5, 15, 30, 45, a n d 60 m i n u t e s ,  drug a d m i n i s t r a t i o n  45,  2.7.1).  from t h e d i a l y s e r  during d i a l y s i s ,  a n d t h e n a t 5,  8 Uremic volunteers ( c r e a t i n i n e 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  10 mg IV MCP 1 h p r i o r to hemodialysis  10 mg IV MCP 16 days p o s t - t r a n s p l a n t  10 mg V MCP 3 months p o s t - t r a n s p l a n t  plasma sampled f o r 24 h and during d i a l y s i s  plasma sampled f o r 24 h (inci. dialysis)  plasma and urine sampled f o r 24 h  Electron-capture gas-chromatographic a n a l y s i s  Scheme 3: S t u d y P r o t o c o l i n U r e m i c P a t i e n t s and K i d n e y Transplant  Recipient  6,  8, 10, 12, a n d 24 h o u r s .  were p r o c e s s e d Section  Again, t h e blood  as f o r t h e normal h e a l t h y  samples  volunteers (see  2.7.1).  2.7.4  Quantitative  Plasma A n a l y s i s  i n Uremic  Patients  A v o l u m e , 0.1 - 0.3 mL, o f t h e p l a s m a s a m p l e s were extracted Sections was  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 ( s e e 2.4.1 a n d 2 . 4 . 2 ) .  used as t h e i n t e r n a l  measured twice, was  Maprotaline  standard.  E a c h s a m p l e was  i n d u p l i c a t e a n d e a c h d u p l i c a t e was i n j e c t e d  2 u L , i n t o t h e ECD-GC f o r a n a l y s i s .  made b y f i t t i n g  t h e area  ratios  Quantitation  f o r t h e HFB  d e r i v a t i v e s o f MCP/MAP t o t h e s t a n d a r d line  H C l (0.4 ug/mL)  curve  regression  ( a r e a r a t i o MCP/MAP v s MCP c o n c e n t r a t i o n ) .  c u r v e s a m p l e s were e x t r a c t e d ,  d e r i v a t i z e d , and  c h r o m a t o g r a p h e d o n t h e same d a y a s t h e v o l u n t e e r The  study  2.7.5  Standard  i n u r e m i c s i s summarized Experimental Protocol  samples.  i n Scheme 3.  f o r t h e Kidney  Transplant  Recipient Subsequent t o t h e f i r s t u r e m i c male v o l u n t e e r kidney transplant.  administration  o f MCP t o a  (BM), t h i s p a t i e n t r e c e i v e d a  The p a t i e n t t h e n r e c e i v e d  two f u r t h e r  d o s e s o f 10 mg I V MCP a s a s h o r t  i n f u s i o n , o v e r 3.5  minutes,  and a g a i n  a t 16 d a y s p o s t - s u r g e r y  after transplantion.  a t 3 months  I n f o r m e d w r i t t e n c o n s e n t was  obtained  on a l l o c c a s i o n s .  biological  sample p r o c e s s i n g  f o r t h e uremic volunteers prior  The sampling p r o t o c o l and  to dialysis.  were t h e same a s o u t l i n e d  r e c e i v i n g t h e d o s e 24 h o u r s  I n 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 h o u r s a s d e s c r i b e d  f o r t h e normal, h e a l t h y  volunteers  (see S e c t i o n  Laboratory  recorded  2.7.1).  from t h e p a t i e n t s *  2.7.6  i n d i c e s were  chart.  Quantitative Analysis  i n Kidney  Transplant  Recipient Plasma, extracted and  0.1 - 0.3 mL, o r 10 u L o f u r i n e  were  a n d d e r i v a t i z e d a s o u t l i n e d i n S e c t i o n s 2.4.1  2.4.2.  Maprotaline  (0.4 ug/mL) was u s e d a s t h e  internal  standard  measured  i n duplicate using  i n t o t h e GC-ECD. made b y f i t t i n g  throughout t h e study.  two i n j e c t i o n s o f 2 u L e a c h  Quantitative t h e area  MCP/MAP t o t h e s t a n d a r d  ratio  determination  curve regression  line  Standard curve  (area  ratio  samples  d e r i v a t i z e d , and chromatographed on t h e  same d a y a s t h e v o l u n t e e r 2.8  Data  2.8.1  Computer Following  o f MCP was  o f t h e HFB d e r i v a t i v e o f  MCP/MAP v s MCP c o n c e n t r a t i o n ) . were e x t r a c t e d ,  E a c h s a m p l e was  samples.  Analysis Fitting  analysis of thebiological  metoclopramide content,  t h e data  samples f o r  were p l o t t e d m a n u a l l y t o  obtain  initial  concentration  k i n e t i c parameter estimates.  The  v s t i m e d a t a were t h e n r u n by  the  m a k i n g p r o g r a m AUTOAN computer g e n e r a t e d and  model.  1974)  by  was  independently  initial  t h e c o m p u t e r p r o g r a m NONLIN final  w h i c h were u s e d  in further  (Dunne,  e s t i m a t e s were (Metzler et a l . ,  estimates of the k i n e t i c  Pharmacokinetic Area  The  to give  parameters  i t e r a t i v e p r o g r a m JANA  f i t the data.  to yield  2.8.2  estimates of the k i n e t i c  using the  to also  then used  Wagner, 1976)  T h e s e e s t i m a t e s were t h e n  c o n f i r m e d by 1985)  (Sedman and  decision  parameters  calculations.  Calculations  under t h e plasma c o n c e n t r a t i o n v s time  determined  by t h e t r a p e z o i d a l  pharmacokinetic distribution, calculations  approximation.  v a l u e s o f c l e a r a n c e , volume  and  bioavailability  g i v e n by G i b a l d i  d i a l y s i s parameters,  and  extraction  are based Perrier  efficiency  c l e a r a n c e , were c a l c u l a t e d by t h e A-V d e s c r i b e d by  Lee  and  Marbury  curve The  of on  standard  (1982). and  dialyzer  difference  (1984) u s i n g t h e  The  method  formula:  a  C  Extraction  efficiency = E = —  - v C  C where: C dialyser  A  U  C  =  a  "  A  AUC  a  U  C  v  a  = p l a s m a MCP c o n c e n t r a t i o n  entering  = p l a s m a MCP c o n c e n t r a t i o n  exiting  a  C dialyser concentration  AUC = area under t h e plasma v s time curve e n t e r i n g t h e d i a l y s e r  concentration  AUC = area under t h e plasma v s time curve e x i t i n g t h e d i a l y s e r  &  v  Dialyser  Clearance  = C l  d  = Q  (1-Hct) E  where: Q = b l o o d f l o w t h r o u g h t h e d i a l y s e r Hct = p a t i e n t s hematocrit E = extraction efficiency 1  T h i s method assumes t h a t t h e b l o o d of metoclopramide i s approximately reported  2.8.3  by Ross-Lee e t a l .  Statistical Statistical  1.  t o plasma  T h i s has been  (1981) i n human  blood.  Tests  e v a l u a t i o n s were p e r f o r m e d u s i n g  a two-sample t - t e s t , compare mean v a l u e s  ratio  paired t-test, between g r o u p s .  o f p < 0.05 t w o - t a i l e d was u s e d .  either  o r one-way ANOVA t o A significance level  3.  RESULTS  3.1  Applicability  o f assay t o uremic  3.1.1  Extraction of blank  serum  plasma  S i n c e many o f t h e components o f u r e m i c p l a s m a  have  b e e n 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 o f many drugs,  aliquots  extracted using  (150, 250, 500 uL) o f u r e m i c p l a s m a  t h e method o f R i g g s e t a l . ( 1 9 8 3 ) , t o  determine p o t e n t i a l retention minutes,  i n t e r f e r e n c e s w i t h MCP o r MAP.  The  t i m e s f o r MCP a n d MAP a r e -9.3 a n d -11.8 respectively.  A s c a n be s e e n  a r e no i n t e r f e r i n g p e a k s t i m e s o f MCP a n d MAP.  eluting  i n Figure  3, t h e r e  close to the retention  O v e r a l l t h e chromatograms o f t h e  e x t r a c t e d uremic plasma  appear  complex t h a n comparable  chromatograms from  healthy  were  t o b e somewhat  less  normal,  volunteers.  3.1.2  Standard Figure  extracted  curve  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 c u r v e  from uremic plasma.  The s l o p e and a r e a  ratios  of t h e p o i n t s agree q u i t e c l o s e l y with those observed from normal  healthy volunteers.  Comparison  with  o b t a i n e d b y R i g g s e t a l . (1983) a l s o d e m o n s t r a t e s correlation.  S i n c e no s i g n i f i c a n t  results good  d i f f e r e n c e s were n o t e d  between t h e s t a n d a r d c u r v e from uremic plasma  and normal  1 min. Figure 3:  1. 2. 3.  Representative chromatograms of blank uremic plasma, extracted as per Riggs et al (1983).  500 uL uremic plasma. 250 uL uremic plasma. 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  p l a s m a , n o r m a l p l a s m a was preparation extraction  of standard  used  curves  i n the  subsequent  simultaneous  o f the p a t i e n t samples.  The  to  the  minimum  2 acceptable  correlation  coefficient  maximum a c c e p t a b l e y - i n t e r c e p t was area  ratio.  point  on  The  the  standard  c u r v e was  10  Normal  pharmacokinetics  3.2.1  Plasma  Kinetics  studied  bioavailability on  plasma data  The  The  are given  the t o t a l  any  o f MCP  were  mean k i n e t i c p a r a m e t e r s f r o m  i n Table  3.  for oral  The  mean v a l u e  c l e a r a n c e , a s compared  undergoes f i r s t - p a s s metabolism.  is  volume o f  28.70 + 6.46  L/h.  c a l c u l a t e d v i a the T h e r e a r e no by  The  a r e a method, i s  statistically  of  the the  i s 0.13 0 + 0.060 h  from e i t h e r  total  of  %.  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 ,  determined  the  highest  of v a r i a t i o n  c l e a r a n c e when c a l c u l a t e d  terminal  of the  pharmacokinetics  e l i m i n a t i o n rate constant  larger values  t h a t MCP  and  0.995 and  a four-way c r o s s o v e r b a s i s i n s i x normal  healthy volunteers.  terminal  -10%  maximum c o e f f i c i e n t  3.2  The  ( r ) was  oral  1  .  with  suggests  Total  body  o r IV  dosing  distribution, 270.26 + 127.70  significant  L.  d i f f e r e n c e s , as  one-way ANOVA, b e t w e e n t h e d o s e g r o u p s f o r  e l i m i n a t i o n rate constant,  body c l e a r a n c e , o r volume o f  bioavailability, distribution.  TABLE 2 Metoclopramide k i n e t i c parameters o b t a i n e d from plasma o f healthyvolunteers DOSE:  5mg S o l .  10mg s o l .  10mg Tab  20mg S o l .  10mg IV  Parameters:  Mean±SD 6  n Ka ( h  _ 1  3  ) 3.21±1.68 3.28± 2.71  a (h-i)  0.6 ±0.3  0.2  0.12± 0.07 0.13± 0.06  3  6  6 3 .29± 1.71  2.78± 0.51 3.64 ±1.93 0.7  0.8± 0.3  7.3 ± 5.3  *  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  CLint (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?  273.2 ±115 318.5 ±166  235.5 ±67  287.9 ±133  242.9 ±128  270.3 ±128  F  r e a  (%) *  83 ± 54  124 ±38  66 ±10  84 ± 44  Determined f o r t h o s e v o l u n t e e r s whose d a t a f i t a two-compartment model (n= 3, 1, 1, 3, 6)  83 ± 4 7  500-  ^  F i g u r e 5:  ^  Mean A r e a u n d e r t h e Plasma C o n c e n t r a t i o n Time C u r v e (+ 1 s.d.) f o r t h e N o r m a l , Healthy Volunteers.  vs  F i g u r e 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 Healthy Volunteer. 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 (CH-O) , 10 mg IV B o l u s (•—•) , 20 mg O r a l S o l u t i o n (•—•) .  Although the  absorption  rate constant,  Ka,  and  two-compartment d i s t r i b u t i o n a l  rate constant,  b e e n c a l c u l a t e d and  t h e i r values  tabulated,  q u i t e v a r i a b l e among t h e v o l u n t e e r s . potential  errors in their  h a v e b e e n p e r f o r m e d on l i n e a r l y with  dose as  Due  e s t i m a t i o n no  them.  AUC  alpha,  have  appear t o  be  to the  shown i n F i g u r e  5 mg  MCP  oral  appears to  i s shown i n F i g u r e  MCP,  and  10  all  mg  MCP  volunteers,  oral  the  plasma data  A  solution.  and  3.2.2  Urinary For  the  data  was  set  (ARE)  o f ARE  regression  In t h i s  figure,  slope of the  IV  and  in  decline and  dose.  The  f i t a  insignificant  l a g time  doses.  Excretion  made f o r 72  then analysed  excreted  received  s o l u t i o n , 10 mg  f r o m most v o l u n t e e r s  normal v o l u n t e e r s  c o l l e c t i o n was  curves  the plasma c o n c e n t r a t i o n s  t w o - c o m p a r t m e n t open m o d e l w i t h oral  time  who  increase proportionately with  gathered  f o l l o w i n g the  oral  t i m e t o p e a k and  phase appear constant AUC's a p p e a r t o  MCP  tests  increase  5.  6 f o r a normal v o l u n t e e r  s o l u t i o n , 20 mg  large  statistical  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 is  the  methods.  a complete  hours f o l l o w i n g dosing.  using  the  Figure  amount r e m a i n i n g 7 shows a  p l o t s f o r a normal h e a l t h y generally  urine The to  be  representative  volunteer.  Linear  Figure  7:  R e p r e s e n t a t i v e Amount R e m a i n i n g t o be Excreted 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 B o l u s (•—•) , 20 mg O r a l S o l u t i o n (•—•) .  resulted kinetic  i n a correlation p a r a m e t e r s from  coefficient  o f > 0.95.  the urine data  Mean  are reported i n  Table 4.  One-way ANOVA shows no s t a t i s t i c a l l y  differences  a c r o s s t h e dose groups.  shows no s i g n i f i c a n t  differences,  parameters determined Therefore,  from  significant  Two-sample  t-testing  f o r comparable  e i t h e r u r i n e o r plasma  the best overall  estimates o f these  parameters  a r e t h e o v e r a l l means w h i c h a r e r e p o r t e d i n T a b l e average The  percent  5.  The  o f d o s e e x c r e t e d i n t a c t was 20.4 + 9.3 %.  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  data.  .  .  .  .  a n d t h e b i o a v a i l a b i l i t y was 0.68 + 0.26.  clearance of t o t a l  (7.6 + 5.3 L/h) a c c o u n t s  Uremic  taken  f o r approximately  clinical  from  Pharmacokinetics 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  the medical  records o f t h e uremic  are d i s p l a y e d i n Table  6.  dialysis  patients are presented  3.3.1  o f t h e uremic  pharmacokinetic  IV d o s e o f MCP Table  9.  shown i n F i g u r e 8.  volunteers t o the  i n Table  7.  Dose  parameters obtained  i n t h e uremic  A typical  results,  The d e t a i l s p e r t a i n i n g  24 h P r e - d i a l y s i s The  25 %  body c l e a r a n c e .  3.3 The  Renal  from  a 10 mg  volunteers are presented i n  plasma c o n c e n t r a t i o n v s time  curve i s  T h e k i n e t i c p a r a m e t e r s show a much  TABLE 3 M e t o c l o p r a m i d e p h a r m a c o k i n e t i c parameters o b t a i n e d from u r i n e d a t a 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  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  0.15±0.04  0.14 ± 0 . 0 5  0.13  0.15 ± 0 . 0 4 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  F  62 ± 2 4  56 ± 12  81 ± 25  76 ± 34  % dose excreted intact j3(h-i)  (%)  6  6  8.7±4.1  7.6 ± 5 . 3 68 ± 2 6  CT>  CAJ  TABLE 4 M e t o c l o p r a m i d e k i n e t i c parameters from t h e cumulated u r i n e and plasma  results  t h e normal, h e a l t h y v o l u n t e e r s DOSE:  5 mg S o l .  10 mg s o l .  10 mg Tab.  20 mg S o l . 10 mg I V  Parameters: n  Mean+SD 6  (3(h~l) 0.14±0.06 F (%)  73±42  3  3  6  0.14 ±0.06  0.13± 0.04  0.14 ±0.05  90±45  74 ±30  80 ±18  6 0.14 ±0.06  0.14 ±0.05 76+38  TABLE 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 PATIENT: AGE ( y r ) WEIGHT (kg) *  Scr (mg/dL) BUN* (mg/dL) A l k Phos (I.U.) H e m a t o c r i t (%) Hemoglobin (g/dL)  PB 34 50. 2  WL 24 50  BM 20 77.3  GM 41 84.5  JS 33 68.7  SS 37 40.3  JT 33 65.2  RT 68 75  11. 0  17.2  13.6  15.1  16.1  11.5  17.4  15. 1  83  73  106 38 14.0 5.4  108 51 15.5 7.2  89 128» 13.0 4.5  82 145 20.6 6.7  82 250» 23.6 7.8  69 79 31. 0 10. 3  -  34. 2 11. 5  -19.2  7.2  1  * Pre-dialysis values * Serum c r e a t i n i n e and b l o o d u r e a n i t r o g e n c o n c e n t r a t i o n s . * Patients are hyperparathyroid.  CTl  TABLE 6 D e t a i l s p e r t a i n i n g t o t h e d i a l y s i s o f uremic p a t i e n t s . PATIENT  PB WL BM GM JS SS JT RT  DIALYSER FILTER TYPE CF CF CF CF CF CF CF CF  1200 1211 1211 1200 1211 1211 1211 1211  DURATION OF DIALYSIS (h) 4.5 4.0 5.1 4.0 4.5 3.5 4.5 4.0  BLOOD FLOW RATE (mL/min) 200 200 200 200 200 200 200 200  The CF 1200 and CF 1211 d i a l y s e r f i l t e r s a r e b o t h h o l l o w f i b r e c a p i l l a r y f l o w cuprophane membranes models ( T r a v e n o l 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 s u r f a c e a r e a o f t h e CF 1200 i s -1.3 s q . m w h i l e t h a t o f t h e CF 1211 i s - 0.9 s q . m.  TABLE 7 Metoclopramide p h a r m a c o k i n e t i c parameters from uremic v o l u n t e e r s 24 h prior to dialysis. PATIENT  alpha (h-l)  i8  (h-D  AUC (ug.h/L)  CLtb (L/h.kg)  Vd a r e a (L/kg)  VC (L/kg)  E (%)  CLd (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 t h e e x t r a c t i o n e f f i c i e n c y o f t h e d i a l y s e r and CLd i s t h e c l e a r a n c e by dialysis.  larger  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  results  1 h Pre-dialysis The  results  from  the  Dose 10 mg  IV MCP  1 h p r i o r to the s t a r t of hemodialysis  is  10.  individual  cases  significant 9,  apparent  as determined decreases  no  effects  3.4.1  12  not  show  the r e s u l t s  i s ineffective  on.MCP  recipient  Plasma The  are presented  although  seen.  at clearing  suggest  in  profile  i n some  statistically displayed i n  by p a i r e d t - t e s t i n g .  Again,  the  terminal  Furthermore, MCP  from  the  t h a t h e m o d i a l y s i s has  little  kinetics.  relevent c l i n i c a l  transplant  Table  from  Pharmacokinetics The  administered  i n t o t a l b o d y c l e a r a n c e and  These r e s u l t s  3.4  do  r a t e c o n s t a n t c a n be  hemodialysis  or  These r e s u l t s ,  different,  difference  elimination  body.  dose  A t y p i c a l plasma c o n c e n t r a t i o n vs time  shown i n F i g u r e 10.  Table  the  o f the normal, h e a l t h y v o l u n t e e r s .  3.3.2  Table  t h a n do  i n Kidney  Transplant Recipient  parameters f o r the  are presented  i n Table  kidney  11.  Kinetics  k i n e t i c paramters obtained are d i s p l a y e d i n and  are presented  the plasma c o n c e n t r a t i o n vs time i n F i g u r e 11.  Prior  to the  profiles  kidney  M 0  I 5  I 10  I 15  I 20  I  25  30  Time,(h) Figure  8:  R e p r e s e n t a t i v e P l a s m a 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 B o l u s Dose G i v e n t o a U r e m i c V o l u n t e e r 24 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 (•—•) , v e n o u s c o n c e n t r a t i o n (D—•) .  TABLE 8 Metoclopramide p h a r m a c o k i n e t i c parameters from uremic v o l u n t e e r s l h prior to dialysis. KINETIC PARAMETER:  alpha (h-1)  P  (h-1)  CLtb AUC (L/h.kg) (ug.h/L)  Vd a r e a (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 r e c e i v e d a k i d n e y a l l o g r a f t p r i o r t o t h e second a d m i n i s t r a t i o n o f metoclopramide. E i s t h e e x t r a c t i o n e f f i c i e n c y o f t h e d i a l y s e r ; CLd i s t h e c l e a r a n c e by dialysis.  IOCH  H  •  O  1 5  i  1  1  1  10  15  20  25  Time^h) F i g u r e 9:  R e p r e s e n t a t i v e P l a s m a 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 B o l u s Dose G i v 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 (•—•) , v e n o u s 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) .  n 30  TABLE 9 C l i n i c a l parameters f o r uremic p a t i e n t BM b e f o r e and a f t e r r e n a l transplantation. PARAMETER: DATE WEIGHT,(kg)  BEFORE Nov. 20/83 77.3  SERUM CREATININE,(mg/dL) BLOOD UREA NITROGEN,(mg/dL)  13.6 106  16 DAYS AFTER Sept. 10/85  3 MONTHS AFTER Dec.  6/85  73.5  84.5  1.8  1.7  35  29  F i g u r e 10:  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 the Kidney Transplant R e c i p i e n t F o l l o w i n g 10 mg IV B o l u s Dose. U r e m i a (•—•) , 15 d a y s 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 of the  k i n e t i c p a r a m t e r s show a p a t t e r n  uremic volunteers,  decreased t o t a l  altered,  as  Urinary The  normal  normals, percent values  the  Figure  11,  and  normal h e a l t h y  following dramatically  fall  within  the  volunteers.  although  i n the i n the  urine apparently  lower range seen  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 o f dose e x c r e t e d  o f MCP.  and  Excretion  e x c r e t i o n o f MCP  levels,  However,  k i n e t i c parameters are  e v i d e n c e d by  r a n g e d i s p l a y e d by 3.4.2  v i z . . extended h a l f - l i f e  body c l e a r a n c e .  t r a n s p l a n t a t i o n the  typical  intact  These r e s u l t s  and  the  reaches  in  e v i d e n c e d by renal  are presented  the  clearance  i n Table  13.  TABLE 10 M e t o c l o p r a m i d e p h a r m a c o k i n e t i c p a r a m e t e r s f o r u r e m i c v o l u n t e e r BM b e f o r e and a f t e r k i d n e y 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" )  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  0.06  0.08  1  CLr,(L/h.kg) CLnr,(L/h/kg)  0.18  0.37  0.73  % dose e x c r eted i n t a c t  0  14  10  C L t b , 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 clearance.  TABLE 11 Metoclopramide P h a r m a c o k i n e t i c parameters from t h e u r i n e o f t h e k i d n e y t r a n s p l a n t recipient PARAMETER  BEFORE  CLr,(L/h.kg) % dose e x c r eted intact  0  16 DAYS AFTER  3 MONTHS AFTER  0.06  0.08  14  10  4. DISCUSSION 4.1  Applicability Analysis  patients  o f drugs  o f Assay t o Uremic  i n biological  samples  can often present d i f f i c u l t i e s  Plasma  from  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 t h e p a t i e n t  samples  may c o n t a i n  from  normal,  s u b s t a n c e s n o t e n c o u n t e r e d i n samples  healthy  volunteers  ( P e r u c c a e t a l . , 1985).  may b e 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 u r e m i c whose p l a s m a excreted  will  contain  o r c a t a b o l i z e d by t h e k i d n e y .  assay s e l e c t i v i t y  d e t e c t i o n mode. ionization  i s a function o f both of the  t h e use o f flame  (FID) i s o f t e n d i f f i c u l t  i n t h e a n a l y s i s o f uremic plasma volatile  The a b i l i t y t o  and t h e s e l e c t i v i t y  For instance,  detection  and l i m i t e d  s i n c e many l o w w e i g h t ,  compounds a r e c a r r i e d o v e r d u r i n g  extraction  patients  many s u b s t a n c e s n o r m a l l y  overcome t h e s e p o t e n t i a l problems the  This  sample  and c a n i n t e r f e r e w i t h d r u g d e t e c t i o n and  quantitation.  The  chromatograms  4) d e m o n s t r a t e 1983)  ( F i g . 3) a n d s t a n d a r d c u r v e ( F i g .  the a b i l i t y  procedure t o detect  selective, samples.  of this  assay  and q u a n t i f y  (Riggs e t a l . .  MCP i n a  a n d l i n e a r manner f r o m u r e m i c p a t i e n t  plasma  The l a c k o f i n t e r f e r e n c e o f t h e c o n t e n t s o f t h e  uremic plasma  likely  stems f r o m t h e u s e o f a d o u b l e  e x t r a c t i o n procedure which  removes a l m o s t a l l p o t e n t i a l l y  interfering the  compounds, a n d / o r t h e r e l a t i v e  e l e c t r o n capture  blank  (ECD).  p l a s m a s a m p l e s was obtained  standard assay  curve  t o be  uL.  This allowed  range of the  duplicates. standard  curve,  another  t o be  method was  experimental  Normal  the  the with  outside as  time  sample.  an  however,  In  two  summary,  adequate t o a c c u r a t e l y o f MCP  i n uremic  plasma  period.  Pharmacokinetics  crossover study  designed  found  quantify trace levels  the e n t i r e  4.2  of  p l a s m a t o m e a s u r e more t h a n  the  and  fell  aliquot  In general,  single  detect  to  u s i n g a more a p p r o p r i a t e v o l u m e , t o p r o v i d e  insufficient  assay  of  of problems  I f the area r a t i o  s e t s o f d u p l i c a t e s f o r any  The  the  ratios  r e s e r v e d enough p l a s m a t o a l l o w  q u a n t i t a t i o n of drug.  t h e r e was  area  of  uremic  i n the middle  p e r f o r m e d o n c e more i n c a s e  the  accurate  200  and  or both  extracted,  e x t r a c t e d f o r most o f t h e  t h a t were a p p r o x i m a t e l y  one  over  S i n c e none o f  c h r o m a t o g r a m s showed i n t e r f e r e n c e , t h e v o l u m e  p l a s m a c h o s e n t o be  be  detector  selectivity  i n the normal h e a l t h y v o l u n t e e r s  t o a n s w e r two  major questions  regarding  was  MCP  pharmacokinetics: 1)  Does MCP  d i s p l a y l i n e a r pharmacokinetics  dose range previous  o f 5 - 20 mg  literature  dose-dependency  ?  claims  of  in spite  of  the  over  the  2)  Given  the experimental  existing  literature  relative  bioavailabilities  The  accumulated  limitations  of  the  what a r e t h e a b s o l u t e o f MCP  and  ?  d a t a p r o v i d e enough i n f o r m a t i o n t o  definitively  a n s w e r t h e s e q u e s t i o n s and  doubt o f the  interpretations  B o t h t h e u r i n e and  of previous  plasma r e s u l t s  existence of linear  pharmacokinetics  examined.  2 this  In Table  t o shed  some  authors.  point to  the  over the dose  range  i s d e m o n s t r a t e d by s e v e r a l  points:  also The  1) The  constant values of beta  f o r each dose  2)  The  constant value 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 o f volume o f  4) The  constant value of  5)  p r o p o r t i o n a l i n c r e a s e i n AUC  The  bioavailability.  plasma c o n c e n t r a t i o n vs time  by  the presence  the p a r a l l e l  similar  time  dosing,  and  kinetics.  w i t h dose  (see  curve  of linear  nature  ( F i g . 6)  kinetics.  also  T h i s can  of the terminal slopes,  be  the  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 the proportionate increases i n both  concentration confirms,  distribution.  5).  Fig.  illustrates seen  level.  and  AUC  w i t h dose.  independently,  The  u r i n e data  the existence of  F i g u r e 7 shows a p a r a l l e l  plasma also  linear  d e c l i n e i n the  amount r e m a i n i n g suggesting there  t o be  excreted  (ARE)  plots  equivalent elimination h a l f - l i v e s .  Further  i s a p r o p o r t i o n a l increase i n the t o t a l  e x c r e t e d unchanged w i t h through  the  addition  dose.  constant values  bioavailability, there  and  i s no  Table  of beta,  percentage  urine.  linear  intact.  In  significant difference obtained  T h u s i t i s d e m o n s t r a t e d t h a t MCP  pharmacokinetics  this  renal clearance,  excreted  statistically  amount  4 a l s o shows  between t h e k i n e t i c parameter v a l u e s and  vs time  from  plasma  undergoes  w i t h i n the dose range from  5-20  mg.  The  previous  finding  p r e v i o u s l y p u b l i s h e d and However, t h e d a t a the previous scrutiny. MCP  widely  two  major c l a i m s  Bateman e t a l . ( 1 9 8 0 ) .  and  f o r the  tablet  observed,  observations  but  cited  an  10 mg,  o f MCP observed  was  and  and  oral  5.4  solution  t o f i v e male v o l u n t e e r s .  statistically  IV d o s e v s  of  G r a f f n e r e t a l . (1979)  unproven,  of d i f f e r e n c e s i n beta h a l f - l i f e  5 mg  close  f o r dose-dependency  o f 20 mg  dose) t h e s e workers concluded half-life  results.  G r a f f n e r e t a l . (1979)  IV d o s e s o f 5 and  slow-release  B a s e d on  accepted  c l a i m s o f dose-dependency deserve  The  administered  contrast to  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  k i n e t i c s h a v e b e e n made by  by  h  and  i s in direct  + 1.8  h  f o r the  (4.4 10 mg  +  1.2 IV  that the e l i m i n a t i o n  dose-dependent.  Additionally,  d i f f e r e n c e i n the percentage  they  excreted  unchanged i n t h e u r i n e  ( 16 + 4 % f o r t h e 5 mg I V d o s e v s  21  + 7 % f o r t h e 10 mg I V d o s e ) a n d a n a v e r a g e  of  150% i n t h e AUC on d o u b l i n g  non-linear  kinetics.  t h e dose as e v i d e n c e o f  There a r e s e v e r a l problems with t h e  i n t e r p r e t a t i o n s o f t h e s e r e s u l t s made b y t h e s e Firstly,  the lack of s t a t i s t i c a l i n t h e mean v a l u e s  Appropriate  t e s t i n g w o u l d h a v e d e m o n s t r a t e d no  significant  d i f f e r e n c e s i n these values.  i s inappropriate.  HPLC-UV d e t e c t i o n a s s a y u s e d , p r o v i d e d t o m e a s u r e MCP  drug a d m i n i s t r a t i o n . period  could  doubling  1971) a n d i n t h i s  observation  increase  noted  case  following the 5  t h e authors mention t h a t t h e  o f t h e dose p r o v i d e s  proportional  8 h after  of the b i o l o g i c a l  explain the shorter h a l f - l i f e Finally,  sufficient  The t r u n c a t i o n o f t h e s a m p l i n g  ( G i b a l d i and W e i n t r a u b ,  mg I V d o s e .  Secondly, the  i n plasma f o r o n l y  can lead t o underestimation  half-life  authors.  demonstration o f  differences  sensitivity  increase  an a p p r o x i m a t e l y  i n plasma c o n c e n t r a t i o n .  contrasts d i r e c t l y with  dose-dependent k i n e t i c s .  This  the claim of  The second s t u d y  claiming  d o s e - d e p e n d e n c y o f MCP k i n e t i c s (Bateman e t a l . . 1980) i s also and  similarly  20 mg a s o r a l  significant  there  MCP was g i v e n  tablets.  B a s e d on  a s 10 mg I V a n d 10 statistically  differences i n elimination  particularly that  flawed.  following the oral  half-life,  doses, t h e authors  a r e d o s e - d e p e n d e n t c h a n g e s i n MCP  claim  elimination  half-life.  While t h e d i f f e r e n c e s  statistically was o n l y  significant,  in  this  of  first-pass  sampling  duration  to significant particularly  The range o f b i o a v a i l a b i l i t y  metabolism the actual  systemic c i r c u l a t i o n 2 0 mg a r e , mg.  observed  following oral  dosing.  following  at least  oral  administration  half-life  estimated  or  I f dose-dependent k i n e t i c s  exist  and a s i g n i f i c a n t  then the h a l f - l i f e the  largest  following  first-pass  of either  effect  Bateman  (198 3 ) ,  from s e v e r a l p h a r m a c o k i n e t i c s t u d i e s ,  benefit  of s t a t i s t i c a l  does n o t obey l i n e a r  MCP u s e d  tests,  evaluate the early  without MCP  This review f a i l s t o l i t e r a t u r e and f a i l s t o  some o b s e r v a t i o n s o f t h e k i n e t i c s i n c a n c e r chemotherapy.  Results  o f 'high-dose" from  i n c a n c e r chemotherapy  i n e x c e s s o f 0.5 mg/kg/h  compares  t o demonstrate t h a t  kinetics.  pharmacokinetic studies doses  d i d exist,  I n a subsequent review o f  results  explain  did in  IV a d m i n i s t r a t i o n would be  l i t e r a t u r e on MCP k i n e t i c s  critically  t h e 10  s i n c e t h e IV r o u t e would p r o v i d e t h e l a r g e s t  amount o f d r u g t o t h e b o d y . the  than that  f o r t h e 10  i s less  dose.  o f 10  3.2 - 6.4 mg a n d , a t most, 9.7 -  The e l i m i n a t i o n  2 0 mg o r a l  This  amounts o f d r u g r e a c h i n g t h e  mg I V d o s e , however,  fact  at the  s t u d y was f r o m 32 - 97 % s u g g e s t i n g t h e e x i s t e n c e  implies that  19.4  lead  i n the estimated h a l f - l i f e  lower dose l e v e l .  and  the entire  6 hours which c o u l d  inaccuracy  do a p p e a r t o b e  employing  ( T a y l o r e t a l . . 1984,  Bryson e t a l . ,  1985) h a v e d e m o n s t r a t e d t h e 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 t h e s e dose  levels.  W r i g h t e t a l . (1984) h a v e d e m o n s t r a t e d d o s e s b e t w e e n 2 0 a n d 100 mg.  Recently,  linear kinetics at  I t cannot be argued  that  MCP a t l o w e r d o s e s  i n humans d i s p l a y s t h e same t y p e o f  nonlinear kinetics  displayed  o b s e r v a t i o n s made b y K a p i l  i n the r a t , since the  e t a l . (1984) a r e  q u a l i t a t i v e l y very different  from t h e c l a i m s o f t h e  a u t h o r s w i t h r e g a r d s t o t h e human work. is  not possible t o  t o humans f o r MCP differ Hori,  from r a t d i r e c t l y  s i n c e t h e m e t a b o l i c p a t t e r n s o f MCP  s u b s t a n t i a l l y b e t w e e n t h e two s p e c i e s 1970; T e n g  The  et a l .  groups  f  (Schuppan  Bateman e t a l . ,  1977).  o f MCP h a v e b e e n et al..  studies suffer  1980; R o s s - L e e  et a l .  f  of their  limitations  are of three types.  results.  p r o c e d u r e s had low s e n s i t i v i t y et al..  1981; B l o c k e t  earlier,  Generally,  a l l of these  these  Many o f t h e e a r l y and/or poor  1979; Bateman e t a l . .  l e d to short  sampling periods  (Gibaldi  and Weintraub,  assay  selectivity  1980).  This  following dosing  w h i c h may n o t 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 parameters  1979;  f r o m l i m i t a t i o n s w h i c h may r e d u c e t h e  credibility  (Schuppan  addressed by s e v e r a l  1979; G r a f f n e r e t a l . .  1 9 8 1 ) . However, a s o u t l i n e d  problem  ( A r i t a and  q u e s t i o n o f t h e a b s o l u t e and r e l a t i v e  bioavailabilities  al.,  extrapolate results  In addition, i t  1971).  kinetic  Several  groups  used a t a b l e t (Schuppan al..  o r c a p s u l e as t h e s o l e o r a l  form  e t a l . . 1979; G r a f f n e r e t a l . . 1979; Bateman e t  1980; R o s s - L e e  e t a l . , 1981).  rate can s i g n i f i c a n t l y affect  b i o a v a i l a b i l i t y would solution.  Finally,  (Schuppan  Since  dissolution  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  doses  dosage  absolute  h a v e b e e n made w i t h a n o r a l  t h e comparison  o f unequal o r a l  and IV  e t a l . . 1979; G r a f f n e r e t a l . . 1979;  B l o c k e t a l . . 1980) was n o t a p p r o p r i a t e s i n c e t h e dose-linearity not  been  fact,  o f MCP k i n e t i c s  established  within this  and t h e e x i s t i n g  dose  range had  e v i d e n c e was, i n  quite t o the contrary.  More s p e c i f i c a l l y t h e w e a k n e s s e s o f e a c h s t u d y a r e as f o l l o w s .  S c h u p p a n e t a l . (1979) u s e d a t h i n  c h r o m a t o g r a p h i c method t o q u a n t i t a t e MCP.  With  layer this  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 entirely allowed  inadequate f o r plasma  (40 ng/mL) a n d t h e i r  These  o f drug e x c r e t i o n  a u t h o r s made t h e i r  unequal  IV and o r a l  existence of linear Additionally, dosage  In t o t a l , only  were t a k e n f r o m e a c h s u b j e c t ,  assessment  only  s a m p l i n g a n d measurement f o r 10 h  following drug administration. samples  assay  f u r t h e r m o r e , no  i n t h e u r i n e was made.  kinetic  comparisons  b a s e d on  doses without demonstration o f t h e kinetics  (50 mg o r a l l y v s 20 mg I V ) .  a c a p s u l e was u s e d a s t h e o r a l  form i n s p i t e  8 plasma  of the fact  that  reference  obtaining  o r making  an o r a l  solution  was p o s s i b l e .  T h e s e a u t h o r s o b s e r v e d 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 t h e b i o a v a i l a b i l i t y of and  a 20 mg MCP  oral  10 mg I V .  tablet  No c l e a r  demonstration  w e r e made b y t h e a u t h o r s . suggested  t h e presence  were t r u e , unequal  with the administration  In fact,  of linear  these  kinetics  authors  of non-linear kinetics.  I f this  t h e n t h e assesment o f b i o a v a i l a b i l i t y  doses  of 5  would have been i m p o s s i b l e .  from  However,  these  w o r k e r s go on t o s u g g e s t t h a t t h e a b s o l u t e bioavailability  i s b e t w e e n 25 - 40 %.  Bateman e t a l . (1980) compared t h e a v a i l a b i l i t y o f 10  a n d 2 0 mg MCP g i v e n a s t h e o r a l  given was  IV.  Due t o i n h e r e n t a s s a y  collected  sampling  t h e AUC f r o m tablet  tablet  i n s e n s i t i v i t y , plasma  l e dt o a requirement  0 to infinity.  solution  dissolution  observed  this  f o r extensive  o f t h e blood curve t o allow c a l c u l a t i o n o f As w e l l ,  dosage form b e f o r e a complete  w i t h an o r a l  w i t h 10 mg  f o r a maximum o f 8 h . C o n s e q u e n t l y ,  approach  extrapolation  tablet  administration assessment  was made  h a s l e d t o some c o n f u s i o n s i n c e  rate can s u b s t a n t i a l l y  alter the  b i o a v a i l a b i l i t y f o ra high c l e a r a n c e drug.  These authors noted differences  substantial  inter-individual  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  of a  32 - 97 %  with  little  Again,  no  explanation  use  Block  was  f o r the  observed v a r i a b i l i t y .  made o f u r i n e  data.  e t a l . (1980) compared t h e  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 o f MCP dosage forms.  significant values. oral  to  12  h  f o l l o w i n g dose thus r e q u i r i n g  In a d d i t i o n , the  of a drop  accuracy  administered equal  oral  spite  of the  existence  30  d r o p s was  is unscientific  substaintially  and  dose.  and  not  allow  Further,  IV d o s e s  of the  equal  accurate  IV v s  f o r r e c t a l l y administered  i n p l a s m a and  bioavailability  However, q u a n t i t a t i o n was  these  MCP.  The vary  knowledge o f  27  mg  the  compare  orally)  in  the  These authors  suggest  f o r m s and  53  MCP.  ECD-GC method t o  oral  dose vs  u r i n e data  of the  quantitate  absolute 10 mg  o n l y p o s s i b l e f o r 10  drug a d m i n i s t r a t i o n ; again independent c o n f i r m a t i o n  t o 10 mg  % f o r o r a l MCP  to determine the  o f a 10 mg  the  since  p o s s i b i l i t y of  of non-linear k i n e t i c s . - 79  AUC  dose o f  t h i s group d i d not  of the  R o s s - L e e e t a l . u s e d an MCP  necessary  s i n c e t h e v o l u m e may  (18 mg  observations  a b i o a v a i l a b i l i t y o f 76 %  allowed  e x t r a p o l a t i o n to obtain the  claim that  and  different  s o l u t i o n a p p e a r s somewhat q u e s t i o n a b l e ,  authors use  in several  T h e i r HPLC method o n l y  q u a n t i t a t i o n up  absolute  was  not  findings using  MCP  IV.  h  after  u s e d as plasma  an  d a t a . These 47  authors claim b i o a v a i l a b i l i t y  o f 77  %  (range  - 114 % ) . These  s t u d i e s were r e v i e w e d by Bateman  true c r i t i c a l  d i s s e c t i o n was  made.  work, W r i g h t e t a l . (1984) h a v e b i o e q u i v a l e n c e b e t w e e n 20 mg as o r a l been  tablet.  No  (1983) b u t  Subsequent  to  no  this  demonstrated  as o r a l  solution  and  20  demonstration of bioequivalence  made a t l o w e r d o s e s , 5 - 20 mg,  which  mg has  a r e more  commonly e n c o u n t e r e d i n a m b u l a t o r y p a t i e n t t h e r a p y .  The p r e s e n t s t u d y a t t e m p t s t o o v e r c o m e t h e p r e v i o u s l y mentioned  limitations  i n s e v e r a l ways.  ECD-GC method i s much more s e n s i t i v e and  The  specific  than  t h e p r e v i o u s a s s a y s 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 longer sampling period. demonstrates the l i n e a r i t y e q u a l d o s e s o f I V MCP s o l u t i o n dosage the o r a l The  form.  solution  results  o f MCP  4,  this  and  available  tablet  5.  absolute b i o a v a i l a b i l i t y  i s also  assesments  study  compares oral  Furthermore, a comparison  and t h e o r a l  and  kinetics  and a r a p i d l y  of the b i o a v a i l a b i l i t y  f r o m T a b l e s 3,  cumulated  In addition,  between  possible. are  clear  The b e s t e s t i m a t e o f t h e o f MCP  d a t a from t h e plasma  i s 78%  using  and u r i n e .  the  I t s h o u l d be  n o t e d , however, t h a t t h e r e i s s i g n i f i c a n t inter-individual bioavailability  variability. of the t a b l e t  The and  relative solution  appears t o  be  -100  % suggesting that tablet  play  a significant  T h i s may o f MCP  result  from  r a t e does  the f a c t  liver  difference  in delivery  only subtly d i f f e r e n t  Shand,  partially  1975).  of the s o l u t i o n t h e y may  t h i s method o f s t u d y . urine data  If this  flow or the r a t e of d e l i v e r y  ( W i l k i n s o n and  The  independently  be  of drug  Thus, and  tablet  obtained  confirm those  are  from  obtained  from  be  and  the  have a p p r o x i m a t e l y approximately  and  the  fact  the  that the t a b l e t  same t i m e  t o p e a k and  same p l a s m a c o n c e n t r a t i o n s . k i n e t i c parameters i n Tables  5 do  not d i f f e r  greatly  from  I n summary, t h e b e t a h a l f - l i f e  d i s t r i b u t i o n being r e l a t i v e l y f o r -21  those  appears  b o d y c l e a r a n c e b e i n g -28.7  accounts  L/h  t o be  and  -5.4  3,  h,  t h e volume  % of the t o t a l best  dose.  (Gibaldi  and  the value of alpha being Perrier,  1982).  with of  Renal Although  explained  f i t a one-compartment open m o d e l , w h i c h from  4,  earlier.  a two-compartment m o d e l i n some c a s e s t h e o r a l  profile result  reported  l a r g e a t -270.1 L.  m o s t o f t h e h e a l t h y v o l u n t e e r d a t a ws using  also  reach  individual  excretion  the  solutions  The  total  to  the  T h i s may  from  to  i f the  indistinguishable  results  is  sensitive  plasma of the normal h e a l t h y v o l u n t e e r s . inferred  MCP.  that the hepatic clearance  c l e a r a n c e w o u l d o n l y be  to hepatic blood  not  i n the absorptive step f o r  i s more i n t e r m e d i a t e t h a n t r u l y h i g h .  t r u e t h e n MCP  the  role  dissolution  l a r g e r than  may Ka  dose  4.3  Uremic  Pharmacokinetics  From t h e i n f o r m a t i o n a v a i l a b l e and  t h o s e t h a t have been p r e v i o u s l y  i n both t h i s completed  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 a p p a r e n t t h a t t h e p h a r m a c o k i n e t i c s o f MCP a l t e r e d by kidney d i s e a s e . 20%  e x c r e t e d unchanged i n t h e u r i n e .  proportion of the oral 4 N  . .  relatively  1977).  MCP  large  renally  impaired patients, Clinical  1979).  suggested  that  u r e m i c s was r e d u c e d  a s an  otherwise.  e f f e c t s t o MCP, patients  Early  particularly  (Caralps,  (Bateman,  body c l e a r a n c e o f MCP i n  approximately  half-life.  those  1979; Bateman  Preliminary investigation the t o t a l  kidney  an much h i g h e r  3 fold  p a t i e n t s w i t h an a t t e n d e n t , p r o p o r t i o n a l elimination  t o occur  i n patients with decreased  p u b l i s h e d i n Lancet, noted  i n uremic  (Webb e t a l . .  w o u l d n o t be e x p e c t e d  however, h a s s u g g e s t e d  incidence o f adverse  has been  w h i c h may o c c u r i n  e x p e r i e n c e u s i n g MCP  antiemetic/antinauseant  Davies,  failure  on t h i s v a l u e  Thus, p h a r m a c o k i n e t i c changes,  o f CNS o r i g i n ,  failure  p r o t e i n bound and r e n a l effect  t o be  i s only  1986).  1980)  a  about  dose o f MCP.is s u l p h a t e d , a t t h e  In addition,  shown t o h a v e l i t t l e  and  i s only  sulphation i s generally believed  slightly,-40%,  reports,  MCP  Although  unaffected i n chronic renal  (Reidenberg,  function,  substantially  .  position,  f o r MCP.  i n normal  reason t o expect  s h o u l d be  I n normals,  study  i n uremic increase i n  T h r e e s t u d i e s , two Lehmann e t a l . . 1985) have examined t h e kinetics  i n humans  and  Tam  ureteral ligation,  administration,  and  5/6  two  range of e x p e r i m e n t a l l y Following  i n AUC  and  (Tam  uranyl step  e t a l . ; 1981),  failure  on  MCP  nitrate  nephrectomy t o p r o v i d e renal  o f MCP  failure  in  a  in  the  T o t a l body c l e a r a n c e  was  animals with  renal  d e c r e a s e d by  a similar proportion.  a  rats.  they noted at l e a s t  elimination h a l f - l i f e  failure.  1981;  e t a l . (1981) u s e d  induced  administration  increase  in rats  influence of renal  i n more d e t a i l .  bilateral  fold  one  (Bateman e t a l . .  two  These r e s u l t s have  b e e n e s s e n t i a l l y p a r a l l e l e d i n t h e work o f Bateman e t a l . (1981) and  Lehmann e t a l . (1985) u s i n g  However, g i v e n and  man  not  be  the the  kinetics 10  mg  same.  failure,  f o l l o w i n g IV and  levels  healthy  approximately  volunteers  increase  No  varying  with  (289.6 +  from t h a t  information  change  was  and  may  the  administration degrees of on  of t o t a l  hemodialysis. body  clearance  % of those seen i n normal  an  attendent,  18.23  L)  was  proportional  Volume not  of  significantly  seen i n normal, h e a l t h y provided  on  the  of  renal  30  in elimination h a l f - l i f e .  distribution different  oral  o f whom were a n e p h r i c  These authors noted a r e d u c t i o n to  for this  Bateman e t a l . (1981) e x a m i n e d  to s i x patients with two  subjects.  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  mechanisms r e s p o n s i b l e  o f MCP  MCP  the  human  extent  volunteers.  of removal  of  MCP b y h e m o d i a l y s i s . increased  These r e s u l t s  i n c i d e n c e o f adverse  suggested  e f f e c t s noted  that the i n uremic  p a t i e n t s g i v e n MCP c o u l d b e r e l a t e d t o a c c u m u l a t i o n o f MCP due t o r e d u c e d  total  body c l e a r a n c e .  Additionally,  t h e s e a u t h o r s s u g g e s t t h a t t h e change i n k i n e t i c s be  solely  e x p l a i n e d by t h e 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  since this  only accounts  clearance. range by  of renal  impairment,  Lehmann e t a l . ( 1 9 8 5 ) .  also  f o r ~20 % o f t o t a l  A more e x t e n s i v e s t u d y ,  p r e v i o u s l y mentioned but  found  d e f i n e d by c r e a t i n i n e  covering a  large completed  These authors c o n f i r m e d t h e  effects  a positive  body  i n humans h a s b e e n  o f uremia  on MCP  kinetics  c o r r e l a t i o n between t o t a l  c l e a r a n c e o f MCP a n d t h e d e g r e e  removal  cannot  body  o f renal.impairment,  c l e a r a n c e ( r = 0.78).  Although  b y h e m o d i a l y s i s was e x a m i n e d , t h e a u t h o r s  interpretation  of this  i s somewhat c o n f u s e d .  They  state  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 a n a d d i t i o n a l increase  as  i n total  body c l e a r a n c e y e t t h a t o f t h e body l o a d  o f MCP.  60 %  i t cleared  relatively  little  In addition,  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) a r e e x t r e m e l y when c o m p a r e d 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 d r u g s . case report  (Berardi et a l . ,  in a single peritoneal 10 u g o f MCP  high  Interestingly,  1986) d e s c r i b i n g MCP  dialysis patient  removal  removed l e s s  f r o m t h e body s u g g e s t i n g t h a t  a  peritoneal  than  dialysis authors total from  i s an  i n e f f i c i e n t method o f r e m o v i n g MCP.  (Lehmann e t a l . 1985)  body c l e a r a n c e n o t e d  speculate that the  i n renal  f a i l u r e may  changes i n r e n a l drug metabolism  recirculation.  However, no  evidence  s t r o n g l y t h a t t h e c h a n g e may  be  Given was  more f u l l y  t o a n s w e r two  suggest  i n r e n a l metabolism,  i n rats  (Kapil  o f MCP  this  e t a l . . 1984). this  major q u e s t i o n s as w e l l  describe the k i n e t i c s  severe renal  to  the authors  t h e p r e v i o u s i n v e s t i g a t i o n s on MCP,  designed  result  i s offered  Although  b e e n shown n o t t o o c c u r  reduced  or enterohepatic  support these speculations.  has  These  study as  to  i n patients with  impairment.  1) What i s t h e e x t e n t o f r e m o v a l  o f MCP  by  hemodialysis? 2)  Does h e m o d i a l y s i s h a v e any  effects  on  the  subsequently displayed kinetics Subsequently, kidney effects MCP  o f MCP?  one  of the uremic  p a t i e n t s (BM)  received a  t r a n s p l a n t which allowed  investigation  of  o f t h e renewed r e n a l  the  f u n c t i o n on t h e d i s p l a y e d  kinetics.  Qualitatively study p a r a l l e l least  the k i n e t i c  results  obtained i n t h i s  those p r e v i o u s l y reported.  a two-fold decrease  in total  There  i s at  body c l e a r a n c e w i t h  a  proportionate  increase  insignificant  change i n volume o f d i s t r i b u t i o n .  uremic p a t i e n t data model.  was  best  f i t by  a two  distributional  rate constant,  much g r e a t e r t h a n t h e b e t a  rate constant.  the  The  in elimination h a l f - l i f e  central  compartment was  average of approximately distribution. kinetic This  data  The i s the  increase  - 40  degree of  compartmental alpha, The  a uremic subject,  be  encountered  % of the  feature of the  implies that, while  substantially  longer  be  "arterial"  may  rationalize  o f MCP  e n t e r i n g and  "venous" c o n c e n t r a t i o n s  by  relatively  concentrations. t h i s problem.  hemodialysis  Two  is relatively  l a r g e amount o f w a t e r may  plasma thereby  concentrating  "venous" c o n c e n t r a t i o n concentration.  The  t h e MCP  appear h i g h e r  possible  pattern the  explanations removal  inefficient, be  a  removed f r o m  and  making  than the may  tubing  plasma as  back i n t o the  occur  exceeding  since the  second e x p l a n a t i o n  may  unpredictable  artificial  leaches  may  leaving  a d h e r e s t o some component o f t h e and  expected  The  sometimes  First,  a  half-lives  reduced doses.  a p p e a r t o b e h a v e i n a somewhat  variation.  at least  even w i t h  plasma c o n c e n t r a t i o n s  uremic  inter-individual  on m u l t i p l e d o s i n g  the  of  of  drug accumulation  manner w i t h  volume  t o t a l volume  excessive  dialyser  very  an  and  of the  was  for  i n t e r m i n a l h a l f - l i f e may  in  A l l the  quite large accounting  most s t r i k i n g  large variablity  two-fold  30  and  be  the  the  "arterial" that  kidney dialysis  MCP or  progresses. MCP, be  rigid  Given the v a r i a b i l i t y dosing  of the  g u i d e l i n e s f o r use  inappropriate.  Following  the  the  accumulation  the  inital  The (Cld)  dosing  a normal l o a d i n g dose,  interval  o f MCP  high  and  uremic p a t i e n t s .  No  may  (E)  and  the  two  MCP  by  distribution  probably  of t h i s  concentration  o f MCP  enough c o n c e n t r a t i o n driving  i n these  administrations dialysis  force for  There are b e t w e e n any  no  on  termination.  drug.  The  with  dosing.  does  not from  significant  two  p a r a m e t e r s between l a c k of removal  to the  h i g h volume  relatively  i n p l a s m a may gradient  noted  r e m o v a l o f MCP  not  an  of  of  low  provide  to provide  significant  pharmacokinetic  noted. the  i s due  both  dialyser clearances  The  statistically  administrations  effect  o f MCP.  a  a  large  adequate  diffusion.  of the  v a r i a t i o n was  to the  may  while  prevent  soon a f t e r  statistically  d i f f e r e n c e s were n o t e d  no  %  c a l c u l a t e d suggest t h a t hemodialysis  contribute significantly  two  (tau)  50  adverse e f f e c t s  concentrations  extraction ratios  of  in renal failure  maintenance dose r e d u c t i o n of a t l e a s t maintaining  kinetics  o f MCP  although  differences  parameters between some  the  intra-individual  This suggests that hemodialysis  k i n e t i c s d i s p l a y e d subsequent t o i t s  has  The  r e s u l t s observed  recipient  provide  speculation. show t h e  The  typical  clearance  from the  some i n t e r e s t i n g i n f o r m a t i o n k i n e t i c s while the pattern  apparantly  transplant,  a p p e a r s t o be  clearance.  On  be  since the  r e l a t e d t o an  irreversible  The  by  uremia  Several  not  contribute  due  species. occur.  due  body  volume  of  unchanged The  deficit  in  rapid total  to  i n the to the  t o the  the  an  not  be  from t h e  seem l i k e l y . and  m e t a b o l i s m o f MCP  r a t may  kinetic data  e x i s t however.  kidney,  directly  lung  Kapil  tissues  i n the  case the  do  extrapolatable  c o n j u g a t e s o f MCP  sulphate  et  rat.  m e t a b o l i c d i f f e r e n c e s between t h e  R e c i r c u l a t i o n of the In t h i s  f o r the  elucidated  metabolism does not  (1984) showed t h a t  man  in total  increased  i s not  possibilities  al.  findings  surgery,  increased.  mechanism r e s p o n s i b l e  c h a n g e s i n u r e m i a c a n n o t be  Extrahepatic  administration  effect.  exact  available.  both  is relatively  change i n k i n e t i c s s u g g e s t s t h a t the created  on  second  improvement  p a t i e n t s ' b o d y w e i g h t had  body c l e a r a n c e  However,  k i n e t i c parameters  the  half-life  uremic  body  3 months f o l l o w i n g  a further  T h i s may  distribution the  total  normal l i m i t s  subsequent a d m i n i s t r a t i o n s . f o l l o w i n g the  the  for  p a t i e n t was  of diminished  kidney transplant  revert to within  and  transplant  w i t h extended plasma h a l f - l i f e .  f o l l o w i n g the  there  kidney  conjugate,  two may  which  The to  accounts  f o r -40  deconjugated process  % w o u l d h a v e t o be  and  then  reabsorbed.  i s accepted to occur  conjugates  o f some d r u g s  excreted i n the In general,  bile,  this  f o r the glucuronide  (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 . addition,  the sulphate conjugate  relatively  chemically stable.  15 m i n u t e s a t 100 acid any  (Arita  1970).  There  of r e c i r c u l a t i o n  vs time p r o f i l e s Thus, such  f  appears  to  be  Hydrolysis occurs within  °C i n t h e p r e s e n c e  et a l .  evidence  o f MCP  In  of 1 N h y d r o c h l o r i c  does not  appear t o  be  i n the plasma c o n c e n t r a t i o n  o b t a i n e d from  the uremic v o l u n t e e r s .  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 o c c u r  at  a somewhat c o n s t a n t r a t e w h i c h i s a t o d d s w i t h  the  accepted pattern of b i l i a r y  plausible  e x p l a n a t i o n may secondary effect  be  recycling.  a c h a n g e i n h e p a t i c MCP  to chronic renal  failure.  on t h e s u l p h a t i o n o f MCP  may  g e n e r a l l y been a c c e p t e d t h a t t h i s relatively  u n a f f e c t e d by u r e m i a  T h i s assumption  A more  metabolism  Although  a  direct  be p o s s i b l e ,  c o n j u g a t i o n pathway i s  (Reidenberg,  i s made on d a t a d e r i v e d f r o m  1977). the  o f a c e t a m i n o p h e n where, a l t h o u g h t h e g l u c u r o n i d e sulphate conjugates  accumulated  i n uremia,  the  o f t h e p a r e n t d r u g were u n a l t e r e d f r o m t h o s e h e a l t h y v o l u n t e e r s (Lowenthal the existence of several degree  et a l •  f  1976).  exist  (Pang,  kinetics and  kinetics  seen  in  However,  sulphotransferses, with  of substrate s p e c i f i c i t y ,  i t has  some  1982).  It  may  be  p o s s i b l e t h a t the  s u l p h a t i o n o f MCP uremia. as  Yet,  evidenced  by  the  and  that  this  specify  1984).  as  Shen  not the r e s u l t liver  between  it  may  a p p e a r t o be  kinetic  evidenced  it  isolated perfused MCP  by  i f such  a change i n h e p a t i c b l o o d  be  a drug  kinetics  rat  with  for  (Gibson,  a l t e r MCP  liver.  are s t r u c t u r a l l y  t o the time  a substance  i s not hemodialysable.  o f u r e m i a may  could  e x t r a c t i o n of  may  the constant values  parameters r e l a t i v e  hemodialysis,  the  available  p o s s i b l e that a s i m i l a r process  However, a s  a  (1985) d e m o n s t r a t e d t h a t some  p r o p r a n o l o l and  be  of  S i m i l a r data  component o f u r e m i c r a t p l a s m a i n h i b i t s i n the  green  suggested  some component o f u r e m i c p l a s m a b u t  T e r a o and  Although  removal  indocyanine  t h e r e s p o n s i b l e mechanism.  1-propranolol  reversible  f o l l o w i n g kidney  These authors  i n r e m o v a l was  o r g a n i c c a t i o n s does not 1986).  such  of  from t h a t seen i n normal  f o r uptake i n t o the  s u b s t r a t e and  be  b e e n shown t h a t t h e r a t e o f  i s decreased  the decrease  sequelae  a l t e r a t i o n may  change i n k i n e t i c s  (Yates e t aL..  competition  not  s e n s i t i v e to the  f o r organic anions  hippurate  livers  the  I t has  liver  be  f o r MCP,  by  transplant.  may  enzymes r e s p o n s i b l e f o r t h e  Alternatively,  kinetics.  occur. of  of onset  i m p a i r s MCP  flow secondary  unrelated,  or  of  clearance additionally  to the  S i n c e MCP  the  sequelae  appears  to  intermediate or high clearance, i t s  are at l e a s t  partially  a function of l i v e r  blood  flow not  ( W i l k i n s o n and in itself  attendent  1979) .  and  Although  cause changes i n l i v e r  and  blood  changes i n drug  offer,  at least  flow,  alter  several  explanation.  (George,  f l o w may  e n t i r e c h a n g e i n MCP  a partial  may  hepatic  clearance  W h i l e t h e change i n h e p a t i c b l o o d f o r the  uremia  f o r example  c a r d i a c d i s e a s e , may  induce  able t o account may  1975).  c o m p l i c a t i o n s of uremia,  hypertension perfusion  Shand,  not  be  kinetics i t  5. 1)  SUMMARY AND  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 2) and  The a b s o l u t e  a t d o s e s b e t w e e n 5 a n d 20 mg.  b i o a v a i l a b i l i t y o f MCP i s -0.78 +  the r e l a t i v e b i o a v a i l a b i l i t y of the solution  tablet  renal  and  i s ~ 1.00.  3)  In spite  o f t h e r e l a t i v e l y minor c o n t r i b u t i o n  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  metoclopramide k i n e t i c s uremia v i z a decrease two-fold with elimination of  CONCLUSIONS  half-life  i n normals,  are substantially  altered i n  i n t o t a l body c l e a r a n c e  an a t t e n d e n t  proportionate  and l i t t l e  of  of at least  increase i n  o r no c h a n g e i n v o l u m e  distribution.  4)  Hemodialysis  i s ineffective  a t removing  m e t o c l o p r a m i d e from t h e body. 5) kinetic 6) to  Hemodialysis  h a s no e f f e c t  on t h e a p p a r e n t  parameters f o l l o w i n g i t s termination. 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MEDICATIONS  2, 1, 3, 1» 1, 2, 1, If  3, 3, 5, 3, 3, 3, 3, 3,  4, 8, 9, 5, 5, 10, 5, 8,  6, 11, 21, 22 11, 12b 10, 12a, 18 7, 11, 12a, 13, 17 9, 12a, 13 12a, 15, 19, 20 11 14  Z-Bec ( m u l t i v i t a m i n ) Beminal c F o r t i s (multivitamin) Folic acid Biotin Vitamin D Calcium Lactate Iron Dextran A m p h o j e l S u s p e n s i o n (A10H ) A m p h o j e l T a b l e t s (A10H ) Robalate (dihydroxyaluminium acetate) B a s a l g e l (A10H ) D o c u s a t e Sodium a) C o l a c e b) R e g u l e x Bisacodyl Pindolol Propranolol Metoprolol Diazepam Secobarbital Cephlexin Captopril Sulfasoxazole P h e n y t o i n Na 3  

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