DMD

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ring, B. J.
Right arrow Articles by Shipley, L. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ring, B. J.
Right arrow Articles by Shipley, L. A.

Vol. 27, Issue 10, 1099-1103, October 1999

Flavin-Containing Monooxygenase-Mediated N-Oxidation of the M1-Muscarinic Agonist Xanomeline

Barbara J. Ring, Steven A. Wrighton, Susanna L. K. Aldridge, Kristian Hansen, Barbara Haehner, and Lisa A. Shipley

Eli Lilly and Co., Indianapolis, Indiana (B.J.R., S.A.W., L.A.S.); Western Maryland College, Westminster, Maryland (S.L.K.A.); Novo Nordisk, Maaloer, Denmark (K.H.); and Indiana University, Indianapolis, Indiana (B.H.)

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 KM (average KM = 5.5 µM) than that observed by the FMO present in human liver microsomes (average KM of 107 µM). 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.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
L. Wang, L. J. Christopher, D. Cui, W. Li, R. Iyer, W. G. Humphreys, and D. Zhang
Identification of the Human Enzymes Involved in the Oxidative Metabolism of Dasatinib: An Effective Approach for Determining Metabolite Formation Kinetics
Drug Metab. Dispos., September 1, 2008; 36(9): 1828 - 1839.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
A. Kousba, R. Soll, S. Yee, and M. Martin
Cyclic Conversion of the Novel Src Kinase Inhibitor [7-(2,6-Dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (TG100435) and Its N-Oxide Metabolite by Flavin-Containing Monoxygenases and Cytochrome P450 Reductase
Drug Metab. Dispos., December 1, 2007; 35(12): 2242 - 2251.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
B. V. Karanam, C. J. Welch, V. G. Reddy, J. Chilenski, M. Biba, and S. Vincent

Drug Metab. Dispos., October 1, 2004; 32(10): 1061 - 1068.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
R. N. Hines, Z. Luo, K. A. Hopp, E. T. Cabacungan, S. B. Koukouritaki, and D. G. McCarver
Genetic Variability at the Human FMO1 Locus: Significance of a Basal Promoter Yin Yang 1 Element Polymorphism (FMO1*6)
J. Pharmacol. Exp. Ther., September 1, 2003; 306(3): 1210 - 1218.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
M. B. Fisher, K. Yoon, M. L. Vaughn, T. J. Strelevitz, and R. S. Foti
Flavin-Containing Monooxygenase Activity in Hepatocytes and Microsomes: In Vitro Characterization and In Vivo Scaling of Benzydamine Clearance
Drug Metab. Dispos., October 1, 2002; 30(10): 1087 - 1093.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
S. Zhou, J. W. Paxton, M. D. Tingle, and P. Kestell
Identification of the Human Liver Cytochrome P450 Isoenzyme Responsible for the 6-Methylhydroxylation of the Novel Anticancer Drug 5,6-Dimethylxanthenone-4-acetic Acid
Drug Metab. Dispos., April 13, 2001; 28(12): 1449 - 1456.
[Abstract] [Full Text]

Home page
 Drug Metab. Dispos.Home page
C. K. Yeung, D. H. Lang, K. E. Thummel, and A. E. Rettie
Immunoquantitation of FMO1 in Human Liver, Kidney, and Intestine
Drug Metab. Dispos., September 1, 2000; 28(9): 1107 - 1111.
[Abstract] [Full Text]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1999 by the American Society for Pharmacology and Experimental Therapeutics.