INFLUENCE OF HEMODIALYSIS AND PERITONEAL DIALYSIS ON THE PHARMACOKINETICS OF CHLORPHENIRAMINE
Abstract
The pharmacokinetic disposition of Chlorpheniramine was evaluated in hemodialysis and peritoneal dialysis patients during the course of a dialysis and dialysis-free period. After intravenous administration of 8 mg of Chlorpheniramine Maleate, the plasma concentration-time profiles showed a post distributive monoexponential elimination with a mean terminal half-life of 17.45 and 11.37 hours in hemodialysis and peritoneal dialysis patients, respectively. Hemodialysis and peritoneal dialysis did not contribute significantly to the elimination of chlorpheniramine since dialysis clearance values accounted for only 2.13 and 4.11% respectively, of the total clearance established during the dialysis period. In orally dosed hemodialysis patients, after the peak plasma concentration was reached, the elimination of chlorpheniramine was biphasic. After an initial rapid decline of plasma levels occurring during the dialysis period, a substantial secondary peak followed by a slow elimination phase was observed during the dialysis-free period. Hemodialysis clearance values were too small to account for the initial rapid decline of plasma levels. The terminal half-lives ranged from 5 to 1474 hours. These plasma concentration-time profiles were indicative of biliary excretion with subsequent enterohepatic recirculation. In orally dosed peritoneal dialysis patients, enterohepatic recirculation was not evident from the plasma concentration-time profiles. After the peak plasma level was reached, a monoexponential decline with a mean terminal half-life of 21.12 hours was observed. The metabolism study suggested the involvement of chlorpheniramine N-oxide as a polar bioreversible metabolite responsible of the recycling phenomenon. The accumulation of that polar metabolite during the dialysis-free period could result in a increased enterohepatic recycling, effecting a longer persistence of drug in the body. The overall bioavailability of chlorpheniramine was evaluated by use of linear system analysis approach in order to distinguish between primary absorption and reabsorption. In hemodialysis patients, the immediate systemic bioavailability, F(,A), was incomplete (0.076 - 0.863) and explained primarily by an hepatic first-pass effect. The fraction recycled, F(,B), ranged from 0.134 to 0.785. In peritoneal dialysis patients, the extent of primary absorption was 1.17 and suggested a reabsorption phenomenon not resolved from the primary absorption.
Degree
Ph.D.
Subject Area
Pharmaceuticals
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