RT Journal Article SR Electronic T1 Multiple forms of cytochrome P450 are involved in the metabolism of ondansetron in humans. JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1225 OP 1230 VO 23 IS 11 A1 C M Dixon A1 P V Colthup A1 C J Serabjit-Singh A1 B M Kerr A1 C C Boehlert A1 G R Park A1 M H Tarbit YR 1995 UL http://dmd.aspetjournals.org/content/23/11/1225.abstract AB Ondansetron is cleared primarily by metabolism in humans, with hydroxylation of the indole moiety in the 7- and 8-positions being the major identified phase I pathways. In vitro studies using lymphoblastoid cell lines expressing single human cytochrome P450 forms and hepatic microsomes were undertaken to investigate the forms involved in the metabolism of ondansetron in humans. The cell lines that expressed CYP1A1, CYP1A2, and CYP2D6 were shown to be capable of metabolizing [14C]ondansetron. Studies with human hepatic microsomes and the specific inhibitors furafylene, quinidine, and ketoconazole confirmed the role of CYP1A2 and CYP2D6 and also demonstrated the involvement of the CYP3A subfamily. The data in this study collectively indicate that multiple cytochrome P450 forms, including CYP1A1, CYP1A2, CYP2D6, and the CYP3A subfamily, are probably involved in the clearance of ondansetron in humans, with no single form of cytochrome P450 dominating the overall metabolism of ondansetron. The role played by CYP2D6 in the metabolism of [14C]ondansetron by human hepatic microsomes in vitro was shown to be minor. This finding is consistent with the lack of bimodality in the clinical pharmacokinetics of ondansetron. It is therefore concluded that ondansetron is metabolized by multiple forms of cytochrome P450, and this limits the likelihood of a clinically relevant interaction with ondansetron by a modulator of a single form of cytochrome P450.