HEPATIC BIOTRANSFORMATION OF DOCETAXEL (TAXOTERE(R)) IN-VITRO - INVOLVEMENT OF THE CYP3A SUBFAMILY IN HUMANS

Docetaxel metabolism mediated by cytochrome P450-dependent monooxygena ses was evaluated in human liver microsomes and hepatocytes. In micros omes, the drug was converted into four major metabolites resulting fro m successive oxidations of the tert-butyl group on the synthetic side chain. Enzyme kinetics appeared to be biphasic with a V-max and appare nt K-m for the high-affinity site of 9.2 pmol/min/mg and 1.1 mu M, res pectively, The intrinsic metabolic clearance in human liver microsomes (V-max/K-m, 8.4 ml/min/g protein) was comparable to that in rat and d og liver microsomes, but lower than in mouse liver microsomes. Althoug h the metabolic profile was identical in all subjects, a large quantit ative variation in docetaxel biotransformation rates was found in a hu man liver microsome library, with a ratio of 8.9 in the highest:lowest biotransformation rates. Docetaxel biotransformation was correlated s ignificantly (0.7698; P < 0.0001) with erythromycin N-demethytase acti vity, but not with aniline hydroxylase or debrisoquine 4-hydroxylase. It was inhibited, both in human hepatocytes and in liver microsomes, b y typical CYP3A substrates and/or inhibitors such as erythromycin, ket oconazole, nifedipine, midazolam, and troleandomycin. Docetaxel metabo lism was induced in vitro in human hepatocytes by dexamethasone and ri fampicin, both classical CYP3A inducers. These data suggest a major ro le of liver cytochrome P450 isoenzymes of the CYP3A subfamily in docet axel biotransformation in humans. Finally, some Vinca alkaloids and do xorubicin were shown to inhibit docetaxel metabolism in human hepatocy tes and Liver microsomes. These findings may have clinical implication s and should be taken into account in the design of combination cancer chemotherapy regimens.