ROLE OF HUMAN CYTOCHROME-P450 3A4 AND 3A5 IN THE METABOLISM OF TAXOTERE AND ITS DERIVATIVES - ENZYME SPECIFICITY, INTERINDIVIDUAL DISTRIBUTION AND METABOLIC CONTRIBUTION IN HUMAN LIVER

Taxotere, a promising anticancer agent, is metabolized almost exclusiv ely in liver and excreted from bile in all species. To determine which cytochrome P450 is involved in taxotere biotransformation, 11 cDNA-ex pressed human cytochrome P450s were examined for their activity in the metabolism of taxotere and its derivatives. Of all P450s, cytochrome P450 3A4 and 3A5 were the most active for the oxidation of taxotere to the primary metabolite RPR104952 and for subsequent oxidation of RPR1 04952 to RPR111059 and RPR111026. RP70617, an epimer of taxotere was a lso metabolized by both P450 3A enzymes to form metabolite XII. The ac tivity of 3A4/5 enzymes for these substrates was 4-50-fold greater tha n the other P450s examined. The K(m)s of 3A4 and 3A5 for taxotere were 0.91 and 9.28 mu M, and V-max for the formation of RPR104952 were 1.1 7 and 1.36 m(-1), respectively. The contribution of the 3A enzyme comp lex to the metabolism of taxotere in human livers from 21 individuals was assessed with the inhibitory monoclonal antibody and ranged from 6 4-93%. The primary oxidative metabolism of taxotere by human liver mic rosomes was well correlated with 3A4-dependent reactions for testoster one 6 beta-hydroxylation (r(2) = 0.84), taxol aromatic hydroxylation ( r(2) = 0.67) and aflatoxin B-1 3 alpha-hydroxylation (r(2) = 0.63); wh ereas a poor correlation was found for reactions specifically catalyse d by other P450s (all r(2) less than or equal to 0.17). The extent of taxotere metabolism also closely correlated with levels of 3A4 enzyme in human livers quantified with immunoblot monoclonal antibody (r(2) = 0.61), These results demonstrate that the P450 3A4 and 3A5 enzymes ar e major determinants in taxotere oxidation and suggest that care must be taken when administering this drug with other drugs that are also s ubstrates for these enzymes. Pharmacogenetics 8:391-401 (C) 1998 Lippi ncott Williams & Wilkins.