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 6α-hydroxytaxol. These metabolites are formed in patients given taxol, with 6α-hydroxytaxol formation representing the principal biotransformation pathway. Metabolite B and 6α-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 6α-hydroxytaxol formation with markers for several P450 enzymes was poor. Chemical inhibitors that selectively inhibited metabolite B formation (troleandomycin, cyclosporine), that selectively inhibited 6α-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 6α-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 6α-hydroxytaxol formation cannot be assigned with certainty.
The United States Adopted Name Council has given the name “paclitaxel” to refer to taxol and TAXOL.
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.