Stereoselective Flunoxaprofen-S-acyl-glutathione Thioester Formation Mediated by Acyl-CoA Formation in Rat Hepatocytes

Abstract

ABSTRACT:Flunoxaprofen (FLX) is a chiral nonsteroidal anti-inflammatory drug that was withdrawn from clinical use because of concerns of potential hepatotoxicity. FLX undergoes highly stereoselective chiral inversion mediated through the FLX-S-acyl-CoA thioester (FLX-CoA) in favor of the (R)-(؊)-isomer. Acyl-CoA thioester derivatives of acidic drugs are chemically reactive species that are known to transacylate protein nucleophiles and glutathione (GSH). In this study, we investigated the relationship between the stereoselective metabolism of (R)-(؊)-and (S)-(؉)-FLX to FLX-CoA and the subsequent transacylation of GSH forming FLX-S-acyl-glutathione (FLX-SG) in incubations with rat hepatocytes in suspension. Thus, when hepatocytes (2 million cells/ml) were treated with (R)-(؊)-or (S)-(؉)-FLX (100

Metabolic Activation of Mefenamic Acid Leading to Mefenamyl-S-Acyl-Glutathione Adduct Formation In Vitro and In Vivo in Rat

“…These results are consistent with results from similar studies with ibuprofen and flunoxaprofen (Grillo and Hua, 2008;Grillo et al, 2010) and point to a general lack of importance for acyl glucuronides mediating the transacylation of GSH. Potentially, metabolism of MFA by acyl-CoA synthetase(s) leads to a buildup of an intermediate MFA-acyl-adenylate.…”

“…at ASPET Journals on May 9, 2018 dmd.aspetjournals.org degradation t 1/2 reported for zomepirac-SG (t 1/2 ϭ 0.8 min; Grillo and Hua, 2003), D-SG (t 1/2 ϭ 1.0 min; Grillo et al, 2003a), flunoxaprofen-SG (t 1/2 ϭ 1.5 min; Grillo et al, 2010), and I-SG (t 1/2 ϭ 4.0 min; Grillo and Hua, 2008). In the present S-acyl-GSH thioester stability experiments, we also tested for the degradation t 1/2 of (R,S)-I-SG and D-SG in incubations with rat hepatocytes where results showed their degradation half-lives to be 2.0 and 0.4 min, respectively.…”

Drug-S-Acyl-Glutathione Thioesters: Synthesis, Bioanalytical Properties, Chemical Reactivity, Biological Formation and Degradation

“…(3); [32]. Employment of this method has resulted in reported synthetic yields of pure S-acyl-GSH thioesters of varied carboxylic acid derivatives ranging from 11 to 40% [7,40,[52][53][54][55]. One very attractive feature of S-acyl-GSH adducts is that they do not require chromatographic purification.…”

“…More recent mechanistic in vitro studies conducted with rat hepatocytes and the profen drugs (R,S)-ibuprofen and (R,S)-flunoxaprofen have shown that both of these chiral drugs form the corresponding S-acyl-GSH thioesters enantioselectively with 25-and 37-fold formed in favor of the (R)-isomers, respectively [7,54]. In those studies, it was shown that the enantioselectivity of S-acyl-GSH thioester formation was consistent with an 11-fold ibuprofenand 12-fold flunoxaprofen-S-acyl-CoA formation also occurring in favor of the (R)-isomers, but not consistent with bioactivation by acyl glucuronidation, where the enantioselectivity of 1--O-acyl glucuronide formation was shown to be ~1 to 2-fold in favor of the (S)-isomers.…”

The Nonenzymatic Reactivity of the Acyl-Linked Metabolites of Mefenamic Acid toward Amino and Thiol Functional Group Bionucleophiles

“…Increasing a-carbon substitution results in decreasing reactivity, which is in agreement with the relative degradation rates associated with acyl glucuronides and assumed to be identical for that of their respective S-acyl-CoA thioesters. Therefore, if MFA toxicity is the result of covalent binding by reactive intermediates, then it is conceivable that the unusually high formation of MFA-GSH in rat hepatocytes (Grillo et al, 2012;Horng and Benet, 2013), compared with diclofenac (Grillo et al, 2003), zomepirac (Olsen et al, 2005), (R)-ibuprofen (Grillo and Hua, 2008), and (R)-flunoxaprofen (Grillo et al, 2010), may be responsible for the tissue injury associated with MFA. This assumption is based on the high covalent binding values in animals dosed with drugs known to cause hepatotoxicity in humans, such as isoniazid (Nelson et al, 1978) and acetaminophen (Matthews et al, 1997).…”