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 car boxylic drugs.
Footnotes
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↵1 Current address: UltraDots, 48611 Warm Springs Blvd., Fremont, CA 94539.
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doi:10.1124/dmd.104.000471.
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ABBREVIATIONS: LC, liquid chromatography; MS, mass spectrometry; MS/MS, tandem mass spectrometry; HPLC, high-performance liquid chromatography; ESI, electrospray ionization; amu, atomic mass unit(s); DMSO-d6, dimethyl-d6 sulfoxide; CID, collision-induced dissociation.
- Received May 13, 2004.
- Accepted September 10, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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