RT Journal Article
SR Electronic
T1 Metabolites of Caspofungin Acetate, a Potent Antifungal Agent, in Human Plasma and Urine
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1274
OP 1278
VO 28
IS 11
A1 Suresh K. Balani
A1 Xin Xu
A1 Byron H. Arison
A1 Maria V. Silva
A1 Amy Gries
A1 Florencia A. DeLuna
A1 Donghui Cui
A1 Prasad H. Kari
A1 Trung Ly
A1 Cornelis E. C. A. Hop
A1 Rominder Singh
A1 Michael A. Wallace
A1 Dennis C. Dean
A1 Jiunn H. Lin
A1 Paul G. Pearson
A1 Thomas A. Baillie
YR 2000
UL http://dmd.aspetjournals.org/content/28/11/1274.abstract
AB 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