In vitro inhibitory effects of troglitazone and its metabolites on drug oxidation activities of human cytochrome P450 enzymes: comparison with pioglitazone and rosiglitazone

1. Investigated were the effects of a new oral antidiabetic drug, troglitazone, and its three metabolites and antidiabetic drug candidates pioglitazone and rosiglitazone on xenobiotic oxidations catalyzed by nine recombinant human cytochrome P450 (P450 or CYP) enzymes and by human liver microsomes. 2. Troglitazone (5 muM) significantly inhibited CYP2C8-dependent paclitaxel 6alpha- hydroxylation and CYP2C9-dependent S-warfarin 7-hydroxylation. On the other hand, pioglitazone and rosiglitazone (50 muM) only slightly inhibited these xenobiotic oxidation activities catalyzed by CYP2C enzymes. 3. The inhibitory potential of troglitazone (50% inhibition concentration, IC50) was ~5 muM for drug oxidations catalyzed by CYP2C9 and CYP2C8 and C20 muM for activities catalyzed by CYP2C19 and CYP3A4 respectively. For the three metabolites of troglitazone tested, a quinone-type metabolite (M3) was the most potent inhibitor for CYP2C enzymes, followed by a sulphate conjugate (M1); effects of a glucuronide (M2) were very...