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Titolo:
Bioactivation of diclofenac via benzoquinone imine intermediates-identification of urinary mercapturic acid derivatives in rats and humans
Autore:
Poon, GK; Chen, Q; Teffera, Y; Ngui, JS; Griffin, PR; Braun, MP; Doss, GA; Freeden, C; Stearns, RA; Evans, DC; Baillie, TA; Tang, W;
Indirizzi:
Merck Res Labs, Dept Drug Metab, Rahway, NJ USA Merck Res Labs Rahway NJ USA k Res Labs, Dept Drug Metab, Rahway, NJ USA Merck Res Labs, Dept Chem, Rahway, NJ USA Merck Res Labs Rahway NJ USAMerck Res Labs, Dept Chem, Rahway, NJ USA
Titolo Testata:
DRUG METABOLISM AND DISPOSITION
fascicolo: 12, volume: 29, anno: 2001,
pagine: 1608 - 1613
SICI:
0090-9556(200112)29:12<1608:BODVBI>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
ANTIINFLAMMATORY DRUG DICLOFENAC; LIVER PROTEIN ADDUCTS; METABOLIC-ACTIVATION; CONJUGATED METABOLITES; HEPATOTOXICITY; HEPATOCYTES; 3A4;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
19
Recensione:
Indirizzi per estratti:
Indirizzo: Tang, W Merck & Co Inc, Dept Drug Metab, POB 2000,RY800-B211, Rahway, NJ 07065 USA Merck & Co Inc POB 2000,RY800-B211 Rahway NJ USA 07065 J 07065 USA
Citazione:
G.K. Poon et al., "Bioactivation of diclofenac via benzoquinone imine intermediates-identification of urinary mercapturic acid derivatives in rats and humans", DRUG META D, 29(12), 2001, pp. 1608-1613

Abstract

The metabolism of diclofenac has been reported to produce reactive benzoquinone Imine intermediates. We describe the identification of mercapturic acid derivatives of diclofenac in rats and humans. Three male Sprague-Dawley rats were administered diclofenac in aqueous solution (pH 7) at 50 mg/kg byintraperitoneal injection, and urine was collected for 24 h. Human urine specimens were obtained, and samples were pooled from 50 individuals. Urine samples were analyzed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). Two metabolites with MH+ ions at m/z 473 were detected in rat urine and identified tentatively as N-acetylcysteine conjugates of monohydroxydiclofenac. Based upon collision-induced fragmentation of the MH+ ions, accurate mass measurements of product Ions, and comparison of LC/MS/MS properties of the metabolites with those of synthetic reference compounds, one metabolite was assigned as 5-hydroxy-4-(N-acetyleystein-S-yl)diclofenac and theother as 4'-hydroxy-3'-(N-acetylcystein-S-yl)diclofenac. The former conjugate also was detected in the pooled human urine sample by multiple reaction-monitoring LC/MS/MS analysis. It is likely that these mercapturic acid derivatives represent degradation products of the corresponding glutathione adducts derived from diclofenac-2,5-quinone imine and 1',4'-quinone Imine, respectively. Our data are consistent with previous findings, which suggest that oxidative bioactivation of diclofenac In humans proceeds via benzoquinone imine intermediates.

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Documento generato il 09/04/20 alle ore 00:23:34