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Hepatic biotransformation of docetaxel (Taxotere®) in vitro: Involvement of the CYP3A subfamily in humans

Institut National de la Santé et de la Recherche Médicale, Antíbes, France.
Cancer Research (Impact Factor: 9.28). 04/1996; 56(6):1296-302.
Source: PubMed

ABSTRACT 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.

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    • "P-gp in the mucosa of the gastrointestinal tract limits the absorption of orally administered docetaxel and mediates its direct excretion into the gut lumen (Sparreboom et al. 1997; Wils et al. 1994). In addition, first-pass elimination by cytochrome P450 (CYP) isoenzymes, mainly CYP3A4 and CYP3A5, in the liver and/or gut wall may also contribute to its low oral bioavailability (Marre et al. 1996; Shou et al. 1998). In a recent publication, it was reported that the expression of CYP3A in the intestine dramatically decreased the absorption of docetaxel into the bloodstream, while hepatic CYP3A expression aided systemic docetaxel clearance in mice (Herwaarden et al. 2007). "
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    • "Docetaxel metabolism requires CYP3A, with evidence for involvement of both CYP3A4 and CYP3A5 (Shou et al, 1998; Cresteil et al, 2002). There have been reports that docetaxel metabolism is inhibited by coadministration with erythromycin, ketoconazole, nifedipine, midazolam , and troleandomycin, and that it is induced by the classic CYP3A inducers, dexamethasone and rifampicin (Marre et al, 1996). Thus, docetaxel metabolism is likely to be influenced by a wide range of coadministered drugs. "
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