Metabolites of caspofungin acetate, a potent antifungal agent, in human plasma and urine

Caspofungin acetate (MK-0991) is a semisynthetic pneumocandin derivative be ing developed as a parenteral antifungal agent with broad-spectrum activity against systemic infections such as those caused by Candida and Aspergillu s species. Following a 1-h i.v. infusion of 70 mg of [H-3]MK-0991 to health y subjects, excretion of drug-related material was very slow, such that 41 and 35% of the dosed radioactivity was recovered in urine and feces, respec tively, over 27 days. Plasma and urine samples collected around 24 h postdo se contained predominantly unchanged MK-0991, together with trace amounts o f a peptide hydrolysis product, M0, a linear peptide. However, at later sam pling times, M0 proved to be the major circulating component, whereas corre sponding urine specimens contained mainly the hydrolytic metabolites M1 and M2, together with M0 and unchanged MK-0991, whose cumulative urinary excre tion over the first 16 days postdose represented 13, 71, 1, and 9%, respect ively, of the urinary radioactivity. The major metabolite, M2, was highly p olar and extremely unstable under acidic conditions when it was converted t o a less polar product identified as N-acetyl-4(S)-hydroxy-4-(4-hydroxyphen yl)-L-threonine gamma-lactone. Derivatization of M2 in aqueous media led to its identification as the corresponding gamma-hydroxy acid, N-acetyl-4(S)- hydroxy- 4-(4-hydroxyphenyl)-L-threonine. Metabolite M1, which was extremel y polar, eluting from HPLC column just after the void volume, was identifie d by chemical derivatization as des-acetyl-M2. Thus, the major urinary and plasma metabolites of MK-0991 resulted from peptide hydrolysis and/or N-ace tylation.