Flavin-containing monooxygenase-mediated Noxidation of the M1-muscarinic agonist xanomeline. Drug Metab Dispos 27

This paper is available online at http://www.dmd.org ABSTRACT: The involvement of flavin-containing monooxygenases (FMOs) in the formation of xanomeline N-oxide was examined in various human and rat tissues. Expressed FMOs formed xanomeline Noxide at a significantly greater rate than did expressed cytochromes P-450. Consistent with the involvement of FMO in the formation of xanomeline N-oxide in human liver, human kidney, rat liver, and rat kidney microsomes, this biotransformation was sensitive to heat treatment, increased at pH 8.3, and inhibited by methimazole. The latter two characteristics were effected to a lesser extent in human kidney, rat liver, and rat kidney microsomes than were observed in human liver microsomes, suggesting the involvement of a different FMO family member in this reaction in these tissues. As additional proof of the involvement of FMO in the formation of xanomeline N-oxide, the formation of this metabolite by a characterized human liver microsomal bank correlated with FMO activity. The FMO forming xanomeline N-oxide by human kidney microsomes exhibited a 20-fold lower K M (average K M ‫؍‬ 5.5 M) than that observed by the FMO present in human liver microsomes (average K M of 107 M). The involvement of an FMO in the formation of xanomeline N-oxide in rat lung could not be unequivocally demonstrated. These data and those in the literature suggest that the increased prevalence of N-oxidized metabolites of xanomeline after s.c. dosing as compared with oral dosing may be due to differences in the affinity of various FMO family members for xanomeline or to differences in exposure to xanomeline that these enzymes receive under different dosing regimens