Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: An in vitro study

被引:168
作者
Obach, RS [1 ]
Cox, LM [1 ]
Tremaine, LM [1 ]
机构
[1] Pfizer Inc, Groton Labs, Pharmacokinet Pharmacodynam & Drug Metab, Groton, CT 06340 USA
关键词
D O I
10.1124/dmd.104.002428
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The oxidative and conjugative metabolism of sertraline was examined in vitro to identify the enzymes involved in the generation of N-desmethyl, deaminated, and N-carbamoyl-glucuronidated metabolites in humans. In human liver microsomes, sertraline was N-demethylated and deaminated by cytochrome P450 ( P450) enzymes with overall K-m values of 98 and 114 muM, 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 K-m values ( 230 - 270 muM). Monoamine oxidase B catalyzed the reaction approximately 3-fold faster than did monoamine oxidase A. Sertraline N-carbamoyl glucuronidation was measured in human liver microsomes in bicarbonate buffer and under a CO2 atmosphere (K-m = 50 muM) 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.
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页码:262 / 270
页数:9
相关论文
共 36 条
[1]   THE ROLE OF CYTOCHROME-P4502D6 IN THE METABOLISM OF PAROXETINE BY HUMAN LIVER-MICROSOMES [J].
BLOOMER, JC ;
WOODS, FR ;
HADDOCK, RE ;
LENNARD, MS ;
TUCKER, GT .
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 1992, 33 (05) :521-523
[2]   Polymorphisms in the CYP 2D6 gene: Association with plasma concentrations of fluoxetine and paroxetine [J].
Charlier, C ;
Broly, F ;
Lhermitte, M ;
Pinto, E ;
Ansseau, M ;
Plomteux, G .
THERAPEUTIC DRUG MONITORING, 2003, 25 (06) :738-742
[3]  
Chun J, 2000, DRUG METAB DISPOS, V28, P905
[4]   Clinical significance of the cytochrome P4502C19 genetic polymorphism [J].
Desta, Z ;
Zhao, XJ ;
Shin, JG ;
Flockhart, DA .
CLINICAL PHARMACOKINETICS, 2002, 41 (12) :913-958
[5]   Clinical pharmacokinetics of sertraline [J].
DeVane, CL ;
Liston, HL ;
Markowitz, JS .
CLINICAL PHARMACOKINETICS, 2002, 41 (15) :1247-1266
[6]   Role of CYP2D6 in the stereoselective disposition of venlafaxine in humans [J].
Eap, CB ;
Lessard, E ;
Baumann, P ;
Brawand-Amey, M ;
Yessine, MA ;
O'Hara, G ;
Turgeon, J .
PHARMACOGENETICS, 2003, 13 (01) :39-47
[7]   O- and N-demethylation of venlafaxine in vitro by human liver microsomes and by microsomes from cDNA-transfected cells:: Effect of metabolic inhibitors and SSRI antidepressants [J].
Fogelman, SM ;
Schmider, J ;
Venkatakrishnan, K ;
von Moltke, LL ;
Harmatz, JS ;
Shader, RI ;
Greenblatt, DJ .
NEUROPSYCHOPHARMACOLOGY, 1999, 20 (05) :480-490
[8]   Human cytochromes mediating sertraline biotransformation: Seeking attribution [J].
Greenblatt, DJ ;
von Moltke, LL ;
Hermatz, JS ;
Shader, RI .
JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY, 1999, 19 (06) :489-493
[9]   The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin [J].
Hamelin, BA ;
Turgeon, J ;
Vallee, F ;
Belanger, PM ;
Paquet, F ;
LeBel, M .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1996, 60 (05) :512-521
[10]  
Kobayashi K, 1999, DRUG METAB DISPOS, V27, P763