DMD Large equally mixed donor pool

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


     

Drug Metabolism and Disposition Fast Forward
First published on November 16, 2004; DOI: 10.1124/dmd.104.002428

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.104.002428v1
33/2/262    most recent
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 Obach, R. S.
Right arrow Articles by Tremaine, L. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Obach, R. S.
Right arrow Articles by Tremaine, L. M.


Received for publication September 27, 2004.
Revised November 4, 2004.
Accepted for publication November 12, 2004.

SERTRALINE IS METABOLIZED BY MULTIPLE CYTOCHROME P450 ENZYMES, MONOAMINE OXIDASES, AND GLUCURONYL TRANSFERASES IN HUMAN: AN IN VITRO STUDY

R. Scott Obach 1*, Loretta M. Cox 1, Larry M. Tremaine 1

1 Pfizer, Inc.

* Address correspondence to: E-mail: ronald_s_obach{at}groton.pfizer.com

Abstract

The oxidative and conjugative metabolism of sertraline was examined in vitro in order to identify the enzymes involved in the generation of N-desmethyl, deaminated, and N-carbamoyl glucuronidated metabolites in human. In human liver microsomes, sertraline was N-demethylated and deaminated by cytochrome P450 enzymes with overall KM values of 98 and 114 µM, respectively, but the intrinsic clearance for N-demethylation was approximately 20-fold greater than for deamination. Using P450 isoform-selective inhibitors and recombinant heterologously expressed enzymes it was demonstrated that several P450 enzymes catalyzed sertraline N-demethylation, with CYP2B6 contributing the greatest extent and lesser contributions from CYP2C19, CYP2C9, CYP3A4, and CYP2D6. For deamination, data supported a role for CYP3A4 and CYP2C19. Purified human monoamine oxidases A and B also catalyzed sertraline deamination with comparable KM values (230-270 µM). MAO-B catalyzed the reaction approximately 3-fold faster than MAO-A. Sertraline N-carbamoyl glucuronidation was measured in human liver microsomes in bicarbonate buffer and under a CO2 atmosphere (KM = 50 µM) and was catalyzed at the fastest rate by recombinant human UGT2B7. The observation that multiple enzymes appear to be involved in sertraline metabolism suggests that there should be no single agent that could substantially alter the pharmacokinetics of sertraline, nor should there be any single drug metabolizing enzyme genetic polymorphism (e.g. CYP2D6, CYP2C19, CYP2C9, UGT1A1) that could profoundly impact the pharmacokinetics of sertraline.


Key words: CYP2B, cytochrome P450, cytochrome P450 catalyzed oxidations, glucuronidation, microsomes, UDP glucuronyltransferases


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
C. Li, M. Kuchimanchi, D. Hickman, L. Poppe, M. Hayashi, Y. Zhou, R. Subramanian, G. Kumar, and S. Surapaneni
In Vitro Metabolism of the Novel, Highly Selective Oral Angiogenesis Inhibitor Motesanib Diphosphate in Preclinical Species and in Humans
Drug Metab. Dispos., July 1, 2009; 37(7): 1378 - 1394.
[Abstract] [Full Text] [PDF]

Home page
 The Annals of PharmacotherapyHome page
M. M Foisy, E. M Yakiwchuk, and C. A Hughes
Induction Effects of Ritonavir: Implications for Drug Interactions
Ann. Pharmacother., July 1, 2008; 42(7): 1048 - 1059.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
R. L. Walsky and R. S. Obach
A Comparison of 2-Phenyl-2-(1-piperidinyl)propane (PPP), 1,1',1''-Phosphinothioylidynetrisaziridine (ThioTEPA), Clopidogrel, and Ticlopidine as Selective Inactivators of Human Cytochrome P450 2B6
Drug Metab. Dispos., November 1, 2007; 35(11): 2053 - 2059.
[Abstract] [Full Text] [PDF]

Home page
 J Clin PharmacolHome page
R. L. Walsky, A. V. Astuccio, and R. S. Obach
Evaluation of 227 Drugs for In Vitro Inhibition of Cytochrome P450 2B6.
J. Clin. Pharmacol., December 1, 2006; 46(12): 1426 - 1438.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
N. N. Bumpus, U. M. Kent, and P. F. Hollenberg
Metabolism of Efavirenz and 8-Hydroxyefavirenz by P450 2B6 Leads to Inactivation by Two Distinct Mechanisms
J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 345 - 351.
[Abstract] [Full Text] [PDF]

Home page
 J PsychopharmacolHome page
C. L. Devane, Z. N. Stowe, J. L. Donovan, D. J. Newport, P. B. Pennell, J. C. Ritchie, M. J. Owens, and J.-S. Wang
Therapeutic drug monitoring of psychoactive drugs during pregnancy in the genomic era: challenges and opportunities
J Psychopharmacol, July 1, 2006; 20(4_suppl): 54 - 59.
[Abstract] [PDF]

Home page
 Drug Metab. Dispos.Home page
R. S. Obach, A. E. Reed-Hagen, S. S. Krueger, B. J. Obach, T. N. O'Connell, K. S. Zandi, S. Miller, and J. W. Coe
METABOLISM AND DISPOSITION OF VARENICLINE, A SELECTIVE {alpha}4{beta}2 ACETYLCHOLINE RECEPTOR PARTIAL AGONIST, IN VIVO AND IN VITRO
Drug Metab. Dispos., January 1, 2006; 34(1): 121 - 130.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
C. L. Shaffer, M. Gunduz, T. N. O'Connell, R. S. Obach, and S. Yee
BIOTRANSFORMATION OF A GABAA RECEPTOR PARTIAL AGONIST IN SPRAGUE-DAWLEY RATS AND CYNOMOLGUS MONKEYS: IDENTIFICATION OF TWO UNIQUE N-CARBAMOYL METABOLITES
Drug Metab. Dispos., November 1, 2005; 33(11): 1688 - 1699.
[Abstract] [Full Text] [PDF]


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

Copyright © 2004 by the American Society for Pharmacology and Experimental Therapeutics.