Metabolic activation of mefenamic acid leading to mefenamyl-S-acyl-glutathione adduct formation in vitro and in vivo in rat

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Mark P GrilloJill C M Wait

Abstract

Carboxylic acid-containing nonsteroidal anti-inflammatory drugs (NSAIDs) can be metabolized to chemically reactive acyl glucuronide and/or S-acyl-CoA thioester metabolites capable of transacylating GSH. We investigated the metabolism of the NSAID mefenamic acid (MFA) to metabolites that transacylate GSH, leading to MFA-S-acyl-GSH thioester (MFA-SG) formation in incubations with rat and human hepatocytes and in vivo in rat bile. Thus, incubation of MFA (1-500 μM) with rat hepatocytes led to the detection of MFA-1-β-O-acyl glucuronide (MFA-1-β-O-G), MFA-S-acyl-CoA (MFA-SCoA), and MFA-SG by liquid chromatography-tandem mass spectrometric analysis. The C(max) of MFA-SG (330 nM; 10-min incubation with 100 μM MFA) was 120- to 1400-fold higher than the C(max) of drug S-acyl-GSH adducts detected from studies with other carboxylic acid drugs to date. MFA-SG was also detected in incubations with human hepatocytes, but at much lower concentrations. Inhibition of MFA acyl glucuronidation in rat hepatocytes had no effect on MFA-SG formation, whereas a 58 ± 1.7% inhibition of MFA-SCoA formation led to a corresponding 66 ± 3.5% inhibition of MFA-SG production. Reactivity comparisons with GSH in buffer showed MFA-SCoA to be 80-fold more reacti...Continue Reading

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Citations

Feb 14, 2013·Chemical Research in Toxicology·Howard Horng, Leslie Z Benet
Nov 13, 2015·Chemical Research in Toxicology·Toni LassilaAri Tolonen
Oct 1, 2016·Chemical Research in Toxicology·Arun TailorB Kevin Park
Aug 27, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Howard Horng, Leslie Z Benet
Jul 4, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Teresa MulderDonglu Zhang

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