BIOTRANSFORMATION OF TAXOIDS BY HUMAN CYTOCHROMES P450 - STRUCTURE-ACTIVITY RELATIONSHIP

The metabolism of paclitaxel and docetaxel by human liver microsomes w as investigated in vitro. The main metabolite of paclitaxel formed in vitro was the 6 alpha-hydroxypaclitaxel: its formation largely exceede d the formation of other metabolites hydroxylated on the lateral chain by rat liver microsomes and initially characterized in rat bile. In c ontrast in vitro studies showed that the initial metabolite of docetax el resulted from the hydroxylation of the tert-butyl of the lateral ch ain at C13 and that the same metabolites were formed in human and anim al models. Comparison of individual CYP protein content of human micro somes and catalytic activities with taxoid biotransformation, showed t hat 2 distinct isoforms were assigned to the 6 alpha-hydroxylation (CY P2C) and to the hydroxylation of the lateral chain (CYP3A4). Chemical and immunological inhibitions confirmed these assumptions The effect o f antineoplastic drugs potentially associated with taxoids during chem otherapy has been tested in vitro on paclitaxel and docetaxel biotrans formations. In the therapeutic range, vincristine, vinblastine, doxoru bicine and cisplatin elicited a moderate or no inhibition of paclitaxe l and docetaxel metabolism, as well as cimetidine, ranitidine and diph enylhydramine used to prevent major side effects associated with taxoi d therapy. In patients given barbiturates, the hydroxylation on the la teral chain of paclitaxel and docetaxel was markedly stimulated and re sulted from the induction of CYP3A isoforms. These results clearly dem onstrated that the biotransformation of paclitaxel and docetaxel by hu man liver microsomes was supported by 2 distinct CYP proteins and that drug interactions could modify the therapeutic efficiency of taxoids during chemotherapy.