METABOLISM OF DOCETAXEL BY HUMAN CYTOCHROMES P450 - INTERACTIONS WITHPACLITAXEL AND OTHER ANTINEOPLASTIC DRUGS

The metabolism of docetaxel by human liver microsomes was investigated in vitro and compared with that of paclitaxel. A main docetaxel metab olite was generated by human liver microsomes in the presence of NADPH : retention time in high pressure liquid chromatography and its ion fr agmentation in mass spectrometry were identical to those of the authen tic derivative hydroxylated at the butyl group of the C-13 side chain. Kinetic measurements and chemical and inmunological inhibitions demon strated that CYP3A was implicated in the hydroxylation of docetaxel: K -m (2 mu m) and V-m values of docetaxel for human liver microsomes wer e comparable to those calculated for the formation of metabolite p-hyd roxyphenyl C3' paclitaxel (M4). Docetaxel hydroxylation correlated onl y with the CYP3A content of microsomes and with CYP3A-dependent 6 beta -hydroxylation of testosterone and 16-hydroxylation of dehydroepiandro sterone. The formation of hydroxydocetaxel was strongly reduced by CYP 3A inhibitors such as ketoconazole, midazolam, erythromycin, testoster one, orphenadrine, and troleandomycin, whereas quinidine (CYP2D6), hex obarbital, tolbutamide, and mephenytoin (CYP2C) had no or little effec t. The hydroxylation of docetaxel exhibited a highly positive correlat ion with the formation of metabolite M4 of paclitaxel (r = 0.929, P < 0.0001, n = 12), but not with its 6-hydroxylation (r = 0.48, P > 0.15) . Docetaxel abolished the hydroxylation of paclitaxel metabolite M4, b ut was totally inactive on its 6 alpha-hydroxylation. Conversely, pacl itaxel reduced significantly the hydroxylation of docetaxel. We examin ed in vitro the possible interaction among docetaxel, paclitaxel, and drugs which could be associated during chemotherapy. Cisplatin, verapa mil, dolorubicin, vinblastine, and vincristine at concentrations usual ly recommended did not markedly modify taxoid metabolism. Ranitidine a nd diphenylhydramine had no effect, but 100 mu m cimetidine partially inhibited the formation of 6 alpha-hydroxypaclitaxel. Pretreatment of patients with barbiturates strikingly stimulated docetaxel hydroxylati on, whereas no acceleration of docetaxel hydroxylation was noticed in a patient receiving steroids.