Assays of CYP2C8- and CYP3A4-mediated metabolism of taxol in vivo and in vitro.

Publisher Summary This chapter describes the assays of CYP2C8– and CYP3A4–mediated metabolism of taxol in vivo and in vitro . Taxol is one of the newer anticancer drugs with a broad spectrum of clinical activity against solid tumors and acute leukemias. The drug is administered by slow intravenous infusion and is cleared from the body by metabolism and biliary/fecal elimination. The principal human metabolite is 6α-hydroxytaxol (6HOT), identified in vitro , using liver microsomes, and in vivo in bile and feces. Other human metabolic pathways include oxidation of a phenyl ring to 3'-( p -hydroxyphenyl)taxol (3'HOT), and oxidation in the 6α- and 3'- p -phenyl positions to a dihydroxylated taxol (DHOT). Using antibodies and recombinant enzymes, it has been concluded that the formation of the main metabolite, 6HOT, is catalyzed by CYP2C8 and one of the minor metabolites, 3'HOT, by CYP3A4, whereas the DHOT formation is dependent on both isoforms. Thus, in vivo and in vitro measurements of taxol metabolism in humans should be a reflection of the activities of these two isoforms.