Miho Kazui

The pharmacokinetics of troglitazone (CAS 97322-87-7, CS-045), a new oral antidiabetic drug for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), were investigated in rats, mice and dogs following oral and intravenous administration of 14C-labeled troglitazone at doses of 5 mg/kg. The absorption rates, calculated from the AUC ratios of total radioactivity after oral and intravenous administration, or from the biliary excretion rate after intraduodenal administration in rats were both as high as 75%. High uptake by the liver, one of the pharmacological target organs, was demonstrated in both rats and mice. Furthermore, in the KK mouse, an obese NIDDM model animal, the radioactivity was incorporated selectively as troglitazone itself to muscle, the peripheral target organ. Troglitazone reversibly bound to serum albumin with a high ratio (> 99%). Troglitazone was mostly metabolized to the conjugates: sulfate (M 1) and glucuronide (M 2). The oxidized metabolite, a quinone-type metabolite (M 3), was found to be further metabolized to the sulfate (U 2). The biliary excretion rates of these conjugates were high in each animal, and the occurrence of enterohepatic circulation of the conjugates was also suggested. Sex differences in pharmacokinetics were observed in rats; i.e. females showed a higher plasma concentration of troglitazone, and a lower concentration of M 1, than males, and they excreted the sex-related metabolite, a hydroxylated M 1 (U 1), in the bile.

Differences in the inhibition of cytochrome P450 activities among thienopyridine antiplatelet agents, ticlopidine, clopidogrel, prasugrel, and the metabolites, 2-oxo-clopidogrel, clopidogrel acid metabolite, deacetylated metabolite of prasugrel (R-95913) and the pharmacologically active metabolites of clopidogrel and prasugrel, were examined using recombinant cytochromes P450 and fluorescent probe substrates. Ticlopidine and clopidogrel inhibited CYP2B6 with IC(50) values of 0.0517+/-0.0323 microM and 0.0182+/-0.0069 microM, respectively, and inhibited CYP2C19 with IC(50) values of 0.203+/-0.124 microM and 0.524+/-0.160 microM, respectively. Ticlopidine also inhibited CYP2D6 (IC(50) of 0.354+/-0.158 microM). In contrast, 2-oxo-clopidogrel, prasugrel and R-95913 were much weaker inhibitors of CYP2B6, CYP2C19 and CYP2D6. The inhibitory effects of all the compounds tested were much weaker on the isoforms other than those indicated above. The active metabolites of clopidogrel and prasugrel and clopidogrel acid metabolite also did not affect the activities of the P450s examined.