A novel bioactivation pathway for 2-[2-(2,6-dichlorophenyl)aminophenyl] ethanoic acid (diclofenac) initiated by cytochrome P450-mediated oxidative decarboxylation

被引：27

作者：

Grillo, Mark P. ^{[1
]}

Ma, Ji ^{[1
]}

Teffera, Yohannes

Waldon, Daniel J.

机构：

[1] Amgen Inc, Dept Pharmacokinet & Drug Metab, San Francisco, CA USA

来源：

DRUG METABOLISM AND DISPOSITION | 2008年 / 36卷 / 09期

关键词：

D O I：

10.1124/dmd.108.021287

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Diclofenac (2-[2-(2,6-dichlorophenyl)aminophenyl]ethanoic acid), a nonsteroidal antiinflammatory drug, undergoes bioactivation by cytochrome P450 oxidation to chemically reactive metabolites that are capable of reacting with endogenous nucleophiles such as glutathione (GSH) and proteins and that may play a role in the idiosyncratic hepatotoxicity associated with the drug. Here, we investigated the ability of diclofenac to be metabolized to 2-(2,6-dichloro-phenylamino) benzyl-S-thioether glutathione (DPAB-SG) in incubations with rat liver microsomes (RLMs) and human liver microsomes (HLMs) fortified with NADPH and GSH. Thus, after incubation of diclofenac (50 mu M)with liver microsomes (1 mg protein/ml), the presence of DPAB-SG was detected in both RLM and HLM incubation extracts by liquid chromatography-tandem mass spectrometry techniques. The formation of DPAB-SG was NADPH-, concentration-, and time-dependent.

引用

页码：1740 / 1744

页数：5

共 9 条

[1] Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity [J].

Boelsterli, UA .

TOXICOLOGY AND APPLIED PHARMACOLOGY, 2003, 192 (03) :307-322

[2] APPLICATION OF CHEMICAL CYTOCHROME-P-450 MODEL SYSTEMS TO STUDIES ON DRUG-METABOLISM .8. NOVEL METABOLISM OF CARBOXYLIC-ACIDS VIA OXIDATIVE DECARBOXYLATION [J].

KOMURO, M ;

HIGUCHI, T ;

HIROBE, M .

BIOORGANIC & MEDICINAL CHEMISTRY, 1995, 3 (01) :55-65

[3] Diclofenac-induced inactivation of CYP3A4 and its stimulation by quinidine [J].

Masubuchi, Y ;

Ose, A ;

Horie, T .

DRUG METABOLISM AND DISPOSITION, 2002, 30 (10) :1143-1148

[4]

Ngui JS, 2000, DRUG METAB DISPOS, V28, P1043

[5]

SMALL RE, 1989, CLIN PHARMACY, V8, P545

[6] The metabolism of diclofenac - Enzymology and toxicology perspectives [J].

Tang, W .

CURRENT DRUG METABOLISM, 2003, 4 (04) :319-329

[7]

Tang W, 1999, DRUG METAB DISPOS, V27, P365

[8] Roles of human hepatic cytochrome P450s 2C9 and 3A4 in the metabolic activation of diclofenac [J].

Tang, W ;

Stearns, RA ;

Wang, RW ;

Chiu, SHL ;

Baillie, TA .

CHEMICAL RESEARCH IN TOXICOLOGY, 1999, 12 (02) :192-199

[9]

Teffera Yohannes, 2008, Drug Metab Lett, V2, P35, DOI 10.2174/187231208783478506

← 1 →