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Drug Metabolism and Disposition Fast Forward
First published on September 15, 2004; DOI: 10.1124/dmd.104.000471

0090-9556/04/3212-1482-1490$20.00
DMD 32:1482-1490, 2004

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IDENTIFICATION OF GLUTATHIONE-DERIVED METABOLITES FROM AN IP RECEPTOR ANTAGONIST

William L. Fitch, Pamela W. Berry, Yaping Tu, Ali Tabatabaei, Lee Lowrie, Francisco Lopez-Tapia, Yanzhou Liu, Dov Nitzan, Mohammad R. Masjedizadeh, and Aravamuthan Varadarajan1

Drug Metabolism and Pharmacokinetics (W.L.F., P.W.B., Y.T., A.T.), Medicinal Chemistry (L.L., F.L.-T., Y.L., D.N.), and Radiochemistry (M.R.M., A.V.) Departments, Roche Palo Alto, LLC, Palo Alto, California

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.

Address correspondence to: William L. Fitch, DMPK Department, Roche Palo Alto, LLC, 3431 Hillview Ave., Palo Alto, CA 94304. E-mail: Bill.fitch{at}roche.com






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