TY - JOUR T1 - Metabolites of Caspofungin Acetate, a Potent Antifungal Agent, in Human Plasma and Urine JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1274 LP - 1278 VL - 28 IS - 11 AU - Suresh K. Balani AU - Xin Xu AU - Byron H. Arison AU - Maria V. Silva AU - Amy Gries AU - Florencia A. DeLuna AU - Donghui Cui AU - Prasad H. Kari AU - Trung Ly AU - Cornelis E. C. A. Hop AU - Rominder Singh AU - Michael A. Wallace AU - Dennis C. Dean AU - Jiunn H. Lin AU - Paul G. Pearson AU - Thomas A. Baillie Y1 - 2000/11/01 UR - http://dmd.aspetjournals.org/content/28/11/1274.abstract N2 - Caspofungin acetate (MK-0991) is a semisynthetic pneumocandin derivative being developed as a parenteral antifungal agent with broad-spectrum activity against systemic infections such as those caused by Candida and Aspergillusspecies. Following a 1-h i.v. infusion of 70 mg of [3H]MK-0991 to healthy subjects, excretion of drug-related material was very slow, such that 41 and 35% of the dosed radioactivity was recovered in urine and feces, respectively, over 27 days. Plasma and urine samples collected around 24 h postdose contained predominantly unchanged MK-0991, together with trace amounts of a peptide hydrolysis product, M0, a linear peptide. However, at later sampling times, M0 proved to be the major circulating component, whereas corresponding urine specimens contained mainly the hydrolytic metabolites M1 and M2, together with M0 and unchanged MK-0991, whose cumulative urinary excretion over the first 16 days postdose represented 13, 71, 1, and 9%, respectively, of the urinary radioactivity. The major metabolite, M2, was highly polar and extremely unstable under acidic conditions when it was converted to a less polar product identified asN-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-l-threonine γ-lactone. Derivatization of M2 in aqueous media led to its identification as the corresponding γ-hydroxy acid,N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-l-threonine. Metabolite M1, which was extremely polar, eluting from HPLC column just after the void volume, was identified by chemical derivatization as des-acetyl-M2. Thus, the major urinary and plasma metabolites of MK-0991 resulted from peptide hydrolysis and/orN-acetylation. The American Society for Pharmacology and Experimental Therapeutics ER -