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Metabolism of Taxol by Human Hepatic Microsomes and Liver Slices: Participation of Cytochrome P450 3A4 and an Unknown P450 Enzyme^{1 ,2}

Division of Clinical Pharmacology, Center for Drug Evaluation and Research, United States Food and Drug Administration, Rockville, Maryland 20857 [J. W. H., A. R., J. M. C.], Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 [B-R. K., F. P. G.]

Incubation of taxol with human hepatic microsomal fractions or freshly isolated human liver slices yields three metabolite high performance liquid chromatography peaks, metabolite A, metabolite B, and 6-hydroxytaxol. These metabolites are formed in patients given taxol, with 6-hydroxytaxol formation representing the principal biotransformation pathway. Metabolite B and 6-hydroxytaxol are shown to be products of different, highly regioselective cytochrome P-450 (P450) enzymes, while metabolite A results from stepwise metabolism by each of these enzymes. Correlation of metabolite B formation with P450 3A markers was good (r² = 0.91–0.94), but the correlation of 6-hydroxytaxol formation with markers for several P450 enzymes was poor. Chemical inhibitors that selectively inhibited metabolite B formation (troleandomycin, cyclosporine), that selectively inhibited 6-hydroxytaxol formation (naringenin, quercetin), or that nonselectively inhibited both pathways (felodipine, ketoconazole) were found. Metabolite B formation was selectively reduced by anti-P450 3A4 antibodies. Expressed human P450 3A4 preparations were efficient catalysts of metabolite B formation; no expressed P450 preparation tested showed a capacity for catalyzing taxane 6-hydroxylation reactions. The combined results of several experimental approaches show that P450 3A4 is the major catalyst of metabolite B formation and that the identity of the P450 enzyme or enzymes responsible for 6-hydroxytaxol formation cannot be assigned with certainty.

¹ The United States Adopted Name Council has given the name "paclitaxel" to refer to taxol and TAXOL.

² Presented at the 5th European Meeting of the International Society for the Study of Xenobiotics, September 1993. This work was supported in part by the United States Food and Drug Administration and USPHS Grants CA44353 and ES00267.

³ To whom requests for reprints should be addressed, at FDA/CDER/ORR/DCP, 8301 Muirkirk Rd., Laurel, MD 20708.

Received 2/10/94. Accepted 5/31/94.

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