Received for publication May 14, 2004.
Revised August 27, 2004.
Accepted for publication September 10, 2004.

Identification of glutathione-derived metabolites from an IP receptor antagonist

Abstract

The metabolic fate of three aromatic carboxylic acid analogs under evaluation as IP receptor antagonists was studied. The initial analog with unsubstituted phenyl groups was subject to a complex set of aromatic oxidative biotransformations. By introduction of 1 or 2 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.

Key words: biliary excretion, drug disposition, glutathione conjugates, mass spectrometry, metabolite indentification, phase II drug metabolism