Hepatic biotransformation of docetaxel (Taxotere) in vitro: involvement of the CYP3A subfamily in humans.
Docetaxel metabolism mediated by cytochrome P450-dependent monooxygenases was evaluated in human liver microsomes and hepatocytes. In microsomes, the drug was converted into four major metabolites resulting from successive oxidations of the tert-butyl group on the synthetic side chain. Enzyme kinetics appeared to be biphasic with a V(max) and apparent K(m) for the high-affinity site of 9.2 pmol/min/mg and 1.1 microm, respectively. 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 dog liver microsomes, but lower in mouse liver microsomes. Although the metabolic profile was identical in all subjects, a large quantitative variation in docetaxel biotransformation rates was found in a human liver microsome library, with a ratio of 8.9 in the highest:lowest biotransformation rates. Docetaxel biotransformation was correlated significantly (0.7698; P < 0.0001) with erythromycin N-demethylase activity, but not with aniline hydroxylase or debrisoquine 4-hydroxylase. It was inhibited, both in human hepatocytes and in liver microsomes, by typical CYP3A substrates and/or inhibitors such as erythromycin, ketoconazole, nifedipine, midazolam, and troleandomycin. Docetaxel metabolism was induced in vitro in human hepatocytes by dexamethasone and rifampicin, both classical CYP3A inducers. These data suggest a major role of liver cytochrome P450 isoenzymes of the CYP3A subfamily in docetaxel biotransformation in humans. Finally, some Vinca alkaloids and doxorubicin were shown to inhibit docetaxel metabolism in human hepatocytes and liver microsomes. These findings may have clinical implications and should be taken into account in the design of combination cancer chemotherapy regimens.
Marre
F
F
Institut National de la Santé et de la Recherche Médicale, Antíbes, France.
Sanderink
G J
GJ
de Sousa
G
G
Gaillard
C
C
Martinet
M
M
Rahmani
R
R
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001711:Biotransformation; D019392:Cytochrome P-450 CYP2E1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000077143:Docetaxel; D004285:Dogs; D004347:Drug Interactions; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010105:Oxygenases / Q000378:metabolism; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D051381:Rats; D013045:Species Specificity; D013379:Substrate Specificity; D043823:Taxoids
D000972:Antineoplastic Agents, Phytogenic; D065607:Cytochrome P-450 Enzyme Inhibitors; D043823:Taxoids; D000077143:Docetaxel; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010105:Oxygenases; D019392:Cytochrome P-450 CYP2E1; D017239:Paclitaxel