Flavin-containing monooxygenase-mediated N-oxidation of the M-1-muscarinicagonist xanomeline

The involvement of flavin-containing monooxygenases (FMOs) in the formation of xanomeline N-oxide was examined in various human and rat tissues. Expre ssed FMOs formed xanomeline N-oxide at a significantly greater rate than di d expressed cytochromes P-450. Consistent with the involvement of FMO in th e formation of xanomeline N-oxide in human liver, human kidney, rat liver, and rat kidney microsomes, this biotransformation was sensitive to heat tre atment, increased at pH 8.3, and inhibited by methimazole. The latter two c haracteristics were effected to a lesser extent in human kidney, rat liver, and rat kidney microsomes than were observed in human liver microsomes, su ggesting the involvement of a different FMO family member in this reaction in these tissues. As additional proof of the involvement of FMO in the form ation of xanomeline N-oxide, the formation of this metabolite by a characte rized human liver microsomal bank correlated with FMO activity. The FMO for ming xanomeline N-oxide by human kidney microsomes exhibited a 20-fold lowe r K-M (average K-M = 5.5 mu M) than that observed by the FMO present in hum an liver microsomes (average K-M of 107 mu 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 incr eased 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 v arious FMO family members for xanomeline or to differences in exposure to x anomeline that these enzymes receive under different dosing regimens.