Metabolism of docetaxel by human cytochromes P450: interactions with paclitaxel 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 metabolite was generated by human liver microsomes in the presence of NADPH: retention time in high pressure liquid chromatography and its ion fragmentation in mass spectrometry were identical to those of the authentic derivative hydroxylated at the butyl group of the C13 side chain. Kinetic measurements and chemical and immunological inhibitions demonstrated that CYP3A was implicated in the hydroxylation of docetaxel: Km (2 microM) and Vm values of docetaxel for human liver microsomes were comparable to those calculated for the formation of metabolite p-hydroxy-phenyl C3' paclitaxel (M4). Docetaxel hydroxylation correlated only with the CYP3A content of microsomes and with CYP3A-dependent 6 beta-hydroxylation of testosterone and 16-hydroxylation of dehydroepiandrosterone. The formation of hydroxydocetaxel was strongly reduced by CYP3A inhibitors such as ketoconazole, midazolam, erythromycin, testosterone, orphenadrine, and troleandomycin, whereas quinidine (CYP2D6), hexobarbital, tolbutamide, and mephenytoin (CYP2C) had no or little effect. The hydroxylation of docetaxel exhibited a highly positive correlation 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, but was totally inactive on its 6 alpha-hydroxylation. Conversely, paclitaxel reduced significantly the hydroxylation of docetaxel. We examined in vitro the possible interaction among docetaxel, paclitaxel, and drugs which could be associated during chemotherapy. Cisplatin, verapamil, doxorubicin, vinblastine, and vincristine at concentrations usually recommended did not markedly modify taxoid metabolism. Ranitidine and diphenylhydramine had no effect, but 100 microM cimetidine partially inhibited the formation of 6 alpha-hydroxypaclitaxel. Pretreatment of patients with barbiturates strikingly stimulated docetaxel hydroxylation, whereas no acceleration of docetaxel hydroxylation was noticed in a patient receiving steroids.
Laboratoire de Pharmacologie et Toxicologie Fondamentales, UPR 8221, Toulouse, France.
I
I
Royer
B
B
Monsarrat
M
M
Sonnier
M
M
Wright
T
T
Cresteil
D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000077143:Docetaxel; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008099:Liver / Q000196:embryology / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000378:metabolism*; D011247:Pregnancy; D043823:Taxoids
D000972:Antineoplastic Agents, Phytogenic; D007527:Isoenzymes; D043823:Taxoids; D000077143:Docetaxel; D003577:Cytochrome P-450 Enzyme System; D017239:Paclitaxel