METABOLIC DISPOSITION OF CLOFIBRATE

In this review, various aspects of the metabolic disposition of Clofibrate are described. Clofibrate circulates in the blood of laboratory animals and man in the form of its active metabolite clofibric acid (CPIB). Levels of CPIB in serum (or plasma), urine or tissues can be measured by ultraviolet spectrometry, a method which provides reliable and reproducible data provided the samples do not contain non-specific UV absorbing substances or interfering drugs. Otherwise, gas-liquid chromatography or high-pressure liquid chromatography are specific and sensitive techniques to assay CPIB. In man, virtually all of an oral dose of Clofibrate is absorbed and excreted in the urine. There is some evidence for enterohepatic circulation. CPIB is eliminated from the serum in two phases, with half-lives of 0.5 hr and 14-22 hr, resp. CPIB is excreted unchanged, as the glucuronide, and as other as yet unidentified metabolites. Bioavailability studies have been conducted with several marketed brands of Clofibrate as well as with compounds which release CPIB in vivo; none of the CPIB derivatives offers any advantage over Clofibrate from the point of view of CPIB bioavailability. CPIB is highly protein bound, and has a volume of distribution (8-9 liters) slightly greater than the volume of plasma albumin; at least some CPIB is taken up into tissue cells. In patients with nephrotic syndrome or chronic renal failure, the percentage of unbound CPIB is increased. The bioavailability of CPIB is unaltered when Clofibrate is administered with the anion exchange resins cholestyramine or colestipol. Although CPIB is capable of displacing warfarin from its protein-binding sites, the studies reported to date imply that the enhanced anticoagulant activity of warfarin in the presence of Clofibrate is the result of a pharmacodynamic rather than pharmacokinetic interaction. Although Clofibrate is an enzyme inducer in rats, there is no evidence that it induces liver microsomal enzymes in man or in monkeys. Species differences in the disposition of Clofibrate are reviewed. The elimination half-life of CPIB varies from 2 hr in mice to 40-50 hr in beagle dogs, and the plasma protein binding ranges from 97% in man to 35% in mice.