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Propafenone pharmacokinetics : GLC-ECD analysis, metabolic induction by phenobarbital in non-smoking and smoking healthy volunteers, protein binding, pharmacodynamics in patients

University of British Columbia

Propafenone (PF) is a new class I antiarrhythmic agent used to treat supraventricular and ventricular tachyarrhythmias. This thesis reports: a) an in vitro protein binding study of PF in normal and uremic sera; b) a drug-drug interaction study of PF and phenobarbital in healthy human subjects and c) a concentration-response relationship study of PF in patients. In order to conduct these studies, it was necessary to develop a sensitive and accurate assay method for the measurement of PF in biological fluids. A capillary column electron-capture detection gas-liquid chromatographic (GLC-ECD) assay was developed for the quantitation of PF. The identity of the derivative formed with heptafluorobutyric anhydride was confirmed by GLC-mass spectrometry. The limit of determination of the assay method was 2.5 ng/mL using 1 mL of serum. The GLC-ECD method developed for the quantitation of PF was further modified to measure the major and active metabolite of PF, 5-hydroxy PF. The serum protein binding of PF was examined and characterized in vitro in serum obtained from healthy human subjects using equilibrium dialysis. Two binding sites, one high-affinity, low-capacity and one low-affinity, high-capacity, were apparent. The serum protein binding of PF was found to be concentration-dependent, with PF free fraction increasing from 0.03 to 0.19 as PF concentration increased from 0.25 to 100 μg/mL. However, no evidence for significant concentration-dependent changes in binding were observed within the PF concentration range of 0.25-1.5 μg/ml, which covered a major portion of the therapeutic concentration range (0.5-2 μg/mL). In pooled uremic serum, the PF free fraction was approximately 50% of that of the PF free fraction in normal serum throughout the concentration range studied (1-5 μg/ml). In serum from patients with chronic renal failure, the increase in PF binding ratio was positively and significantly correlated with the increase in serum α₁-acid glycoprotein (AAG) concentration, suggesting that AAG is an important binding protein for PF in serum. The effect of enzyme induction on the pharmacokinetics of PF and its major and active metabolite, 5-hydroxy PF, was studied in eight healthy non-smoking and eight healthy heavy cigarette smoking Caucasian males (age 20-45 y). Each subject received a single oral dose of PF (300 mg) on two occasions, separated by 23 days of phenobarbital treatment (100 mg daily at bedtime). Except for two smokers who were 'slow' metabolizers, all nonsmoking and smoking subjects were 'rapid' metabolizers (intrinsic clearance, CL[sub int] >0.5 L/min) Since there was great intersubject variability in most kinetic parameters calculated, each subject served as his own control. Phenobarbital induced hepatic microsomal enzymes and enhanced the extent of the first-pass metabolism of PF. There was a significant increase in CL[sub int] after phenobarbital treatment. The increase in CL[sub int] ranged from 10-831% in the non-smokers and 23-450% in the smokers, resulting in a substantial decrease in the systemic availability, as measured by a reduction in PF peak concentration (C[sub max]) and the area under the serum concentration-time curve (AUC). The decrease in C[sub max] ranged from 0-87% in the non-smokers and 8-85% in the smokers while the decrease in AUC ranged from 10-89% in the non-smokers and 19-82% in the smokers. Except for two smoking subjects, the percent decrease in serum AUC was similar to the percent decrease in salivary AUC noted after enzyme induction in the non-smoking and the smoking subjects. Phenobarbital treatment did not lead to increases in the serum concentration, C[sub max] or the AUC of 5-hydroxy PF. Furthermore, there was no observed increase in the renal excretion of the conjugates of either 5-hydroxy PF or 5-hydroxy-4-methoxy PF, a subsequent metabolite of 5-hydroxy PF. Twenty-three days of phenobarbital treatment did not cause any change in PF free fraction or serum AAG concentration in the non-smoking and the smoking subjects. A wide range in the extent of metabolic induction of PF by phenobarbital, expressed as percent decrease in AUC, was observed in the non-smokers and the smokers, and in Vapid' and 'slow' metabolizers. Enzyme induction did not convert ‘slow' metabolizers of PF to 'rapid' metabolizers. Furthermore, the extent of metabolic induction of PF by phenobarbital was independent of the individual's polymorphic phenotype, serum phenobarbital concentration or the apparent initial ability of the individual's liver to metabolize drugs, i.e., CL[sub int] control. When compared to the non-smokers, heavy cigarette smokers had a significantly larger CL[sub int], a lower C[sub max] and a smaller AUC. While smoking did appear to increase the clearance of PF, it is difficult to conclude that smoking induced the metabolism of PF, due to the small sample size and the lack of comparison of smokers (serving as their own experimental control) under a nonsmoking circumstance. The concentration-response relationship of PF was studied in 10 patients (age 30-71 y) receiving PF (mean daily oral dose = 650 mg) for treatment of supraventricular arrhythmias. The QRS width measured from signal-averaged electrocardiograms (150 beats) was used as an indicator of the antiarrhythmic response of PF. The correlation between QRS width and several parameters such as PF serum concentration, 5-hydroxy PF serum concentration and serum AAG concentration was examined. Each of these parameters seemed to contribute to or influence the overall pharmacological effect of PF. It was possible to predict QRS width from the values of these parameters using an equation developed from multiple stepwise regression. The equation was described as Y = 0.5X₁ + 4.5X₂ + 347X₃ + 79 where Y was QRS width, X₁ was log PF serum concentration, X₂ was log 5-hydroxy PF serum concentration and X₃ was the reciprocal of serum AAG concentration.

Text

2010-10-10

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http://hdl.handle.net/2429/29064

Pharmaceutical Sciences

University of British Columbia

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