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Flavin-containing monooxygenase-mediated N-oxidation of the M(1)-muscarinic agonist xanomeline.
Drug Metab Dispos. 1999 Oct; 27(10):1099-103.DM

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 N-oxide 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 microM) than that observed by the FMO present in human liver microsomes (average K(M) of 107 microM). 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.

Authors+Show Affiliations

Eli Lilly and Co., Indianapolis, Indiana 46285, USA. ring_barbara_j@lilly.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

10497134

Citation

Ring, B J., et al. "Flavin-containing Monooxygenase-mediated N-oxidation of the M(1)-muscarinic Agonist Xanomeline." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 27, no. 10, 1999, pp. 1099-103.
Ring BJ, Wrighton SA, Aldridge SL, et al. Flavin-containing monooxygenase-mediated N-oxidation of the M(1)-muscarinic agonist xanomeline. Drug Metab Dispos. 1999;27(10):1099-103.
Ring, B. J., Wrighton, S. A., Aldridge, S. L., Hansen, K., Haehner, B., & Shipley, L. A. (1999). Flavin-containing monooxygenase-mediated N-oxidation of the M(1)-muscarinic agonist xanomeline. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 27(10), 1099-103.
Ring BJ, et al. Flavin-containing Monooxygenase-mediated N-oxidation of the M(1)-muscarinic Agonist Xanomeline. Drug Metab Dispos. 1999;27(10):1099-103. PubMed PMID: 10497134.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Flavin-containing monooxygenase-mediated N-oxidation of the M(1)-muscarinic agonist xanomeline. AU - Ring,B J, AU - Wrighton,S A, AU - Aldridge,S L, AU - Hansen,K, AU - Haehner,B, AU - Shipley,L A, PY - 1999/9/25/pubmed PY - 1999/9/25/medline PY - 1999/9/25/entrez SP - 1099 EP - 103 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 27 IS - 10 N2 - 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 N-oxide 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 microM) than that observed by the FMO present in human liver microsomes (average K(M) of 107 microM). 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. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/10497134/Flavin_containing_monooxygenase_mediated_N_oxidation_of_the_M_1__muscarinic_agonist_xanomeline_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10497134 DB - PRIME DP - Unbound Medicine ER -