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Research ArticleArticle

Interaction of γ-Glutamyltranspeptidase with Ibuprofen-S-Acyl-Glutathione In Vitro and In Vivo in Human

Mark P. Grillo, Michelle Tadano Lohr and Smriti Khera
Drug Metabolism and Disposition January 2013, 41 (1) 111-121; DOI: https://doi.org/10.1124/dmd.112.048645
Mark P. Grillo
Departments of Pharmacokinetics and Drug Metabolism (M.P.G., M.T.L.) and Medicinal Chemistry (S.K.), Amgen Inc., South San Francisco, California
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Michelle Tadano Lohr
Departments of Pharmacokinetics and Drug Metabolism (M.P.G., M.T.L.) and Medicinal Chemistry (S.K.), Amgen Inc., South San Francisco, California
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Smriti Khera
Departments of Pharmacokinetics and Drug Metabolism (M.P.G., M.T.L.) and Medicinal Chemistry (S.K.), Amgen Inc., South San Francisco, California
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Abstract

Ibuprofen is metabolized to chemically reactive acyl glucuronide and S-acyl-CoA metabolites that are proposed to transacylate glutathione (GSH) forming ibuprofen-S-acyl-GSH (I-SG) in vivo. Herein, we report the detection of novel metabolites of ibuprofen, namely ibuprofen-N-acyl-cysteinylglycine (I-N-CG), ibuprofen-N-acyl-cysteine (I-N-C), and the mercapturic acid conjugate, ibuprofen-S-acyl-N-acetylcysteine (I-S-NAC), in urine from an ibuprofen-dosed volunteer. Thus, analysis of ibuprofen-dosed (Advil, 800 mg, Pfizer, Madison, NJ) human urine extracts by sensitive liquid chromatography tandem mass spectrometric detection resulted in the identification of I-N-CG, I-N-C, and I-S-NAC derivatives as minor metabolites (6.0, 1.7, and 0.2 µg excreted 10-hours postadministration, respectively). I-N-CG is proposed to be formed from the degradation of I-SG by γ-glutamyltranspeptidase (γ-GT)-mediated cleavage of the γ-glutamyl group, leading to an unstable ibuprofen-S-acyl-cysteinylglycine (I-S-CG) intermediate that undergoes spontaneous S to N intramolecular rearrangement. Then, dipeptidase-mediated cleavage of glycine from I-N-CG leads to the formation of I-N-C. Treatment of racemic I-SG (100 µM) in vitro with commercially available bovine kidney γ-GT (0.1 units/ml) in buffer at pH 7.4 and 37°C resulted in its complete degradation, yielding (R)- and (S)-I-N-CG after 15 minutes of incubation. In vitro enzyme kinetic studies with bovine kidney γ-GT incubated separately with (R)- and (S)-I-SG isomers revealed no enantioselective degradation. Results from these studies provided evidence that ibuprofen is metabolized in human to reactive transacylating-type intermediates that react with GSH, forming I-SG thioester that, following degradation by γ-GT and dipeptidase enzymes and following S to N intramolecular rearrangement, leads to the urinary excretion of the I-N-CG and I-N-C amide-linked conjugates, respectively.

Footnotes

  • dx.doi.org/10.1124/dmd.112.048645.

  • Received August 24, 2012.
  • Accepted October 10, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (1)
Drug Metabolism and Disposition
Vol. 41, Issue 1
1 Jan 2013
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Research ArticleArticle

Interaction of γ-GT with Ibuprofen-S-Acyl-Glutathione

Mark P. Grillo, Michelle Tadano Lohr and Smriti Khera
Drug Metabolism and Disposition January 1, 2013, 41 (1) 111-121; DOI: https://doi.org/10.1124/dmd.112.048645

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Research ArticleArticle

Interaction of γ-GT with Ibuprofen-S-Acyl-Glutathione

Mark P. Grillo, Michelle Tadano Lohr and Smriti Khera
Drug Metabolism and Disposition January 1, 2013, 41 (1) 111-121; DOI: https://doi.org/10.1124/dmd.112.048645
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