Identification of glutathione-derived metabolites from an IP receptor antagonist

Drug Metabolism and Disposition : the Biological Fate of Chemicals
William L FitchAravamuthan Varadarajan

Abstract

The metabolic fate of three aromatic carboxylic acid analogs under evaluation as prostaglandin I2-preferring receptor antagonists was studied. The initial analog with unsubstituted phenyl groups was subject to a complex set of aromatic oxidative biotransformations. By introduction of one or two fluorines, these pathways were inhibited. All three analogs were metabolized to a wide variety of carboxylic acid conjugates. Among these were several conjugates formed via secondary metabolism and oxidation of acyl glutathione intermediates. Two of the structure classes, represented by the S-methyl-N-cysteinylglycine conjugate and the N-cysteinylglycine disulfide conjugates, have been described only rarely in the literature. The related S-oxide of the S-methyl-N-cysteinylglycine conjugate and the N,S-bis-acyl derivative of cysteinylglycine are here described for the first time as conjugate metabolites of carboxylic drugs.

References

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Dec 18, 2001·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mark P Grillo, Leslie Z Benet
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Oct 23, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mark P Grillo, Fengmei Hua

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Citations

Oct 19, 2006·Pharmaceutical Research·Yuan ChenWilliam L Fitch
Aug 9, 2011·Chemical Reviews·Takako Hirata, Shuh Narumiya
May 9, 2006·Nature Biotechnology·Yingying GuoGary Peltz
May 9, 2014·Bioanalysis·Jan ScicinskiWilliam L Fitch
May 26, 2015·Expert Opinion on Drug Metabolism & Toxicology·Mark P Grillo
Jul 25, 2009·British Journal of Pharmacology·R L JonesD F Woodward
Apr 28, 2007·Rapid Communications in Mass Spectrometry : RCM·William L FitchLudmila Alexandrova
Oct 12, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mark P GrilloSmriti Khera
Dec 31, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kazuko InoueTsutomu Yoshimura

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