Dose-dependent pharmacokinetics of clofibric acid in the non-human primate

The pharmacokinetics of clofibric acid (CPIB, the active metabolite of clofibrate) has been studied in two species of non-human primate after administration by two routes at three dose levels. Plasma CPIB concentrations were determined by HPLC. In both the cynomolgus monkey and the baboon, the systemic availability of orally administered CPIB did not differ significantly from 100%; the rates of bioavailability, however, showed a dose-related trend. At the lowest dose level (15 mg/kg), the plasma concentration-time profile appeared to follow first order kinetics, with an apparent t1/2 of 1 h; at dose levels which might be used in toxicity studies (45 and 150 mg/kg) the apparent t1/2 was longer, indicating dose-related trends by both routes of administration. The pharmacokinetics of CPIB are therefore non-linear over the dose range considered. CPIB protein binding was concentration-dependent over the range 50-700 micrograms/ml. Re-estimation of kinetic parameters in terms of free drug concentration did not remove the non-linearity. It is concluded that the pharmacokinetics of CPIB in the non-human primate are dose-dependent but that the extent of absorption of an oral dose was independent of dose level over the range studied.