Identification of Glutathione Conjugate Formed from Loxistatin in Rats

Abstract
1. The metabolic fate of loxistatin, ethyl-(+)-(2S,3S)-3-[(S)-3-methyl-1-(3-methyl-butulcarbamoyl)butylcarbamoyl]-2-oxiranecarboxylate, was studied in rats. 2. Following oral administration of 14C-loxistatin the major part of radioactivity was eliminated via the bile into the faeces. 3. The major metabolites in bile were isolated and identified as glutathione and cysteine conjugates of loxistatin acid, by chromatography, proton n.m.r. spectroscopy and mass spectrometry and comparison with those of the authentic reference compounds. 4. Formation of the glutathione conjugate was also demonstrated in vitro by incubation of 14C-loxistatin acid with rat liver cytosol and glutathione.