Balani S K, Xu X, Arison B H, Silva M V, Gries A, DeLuna F A, Cui D, Kari P H, Ly T, Hop C E, Singh R, Wallace M A, Dean D C, Lin J H, Pearson P G, Baillie T A
Department of Drug Metabolism Merck Research Laboratories West Point, Pennsylvania, USA.
Drug Metab Dispos. 2000 Nov;28(11):1274-8.
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 Aspergillus species. Following a 1-h i.v. infusion of 70 mg of [(3)H]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 as N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-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 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/or N-acetylation.
醋酸卡泊芬净（MK - 0991）是一种半合成的棘白菌素衍生物，正在开发用作肠胃外抗真菌药物，对念珠菌和曲霉菌等引起的全身性感染具有广谱活性。给健康受试者静脉输注70毫克[(3)H]MK - 0991 1小时后，药物相关物质的排泄非常缓慢，以至于在27天内，分别有41%和35%的给药放射性在尿液和粪便中回收。给药后约24小时收集的血浆和尿液样本中主要含有未变化的MK - 0991，以及痕量的一种肽水解产物M0，一种线性肽。然而，在随后的采样时间，M0被证明是主要的循环成分，而相应的尿液标本主要含有水解代谢产物M1和M2，以及M0和未变化的MK - 0991，给药后前16天它们的累积尿排泄分别占尿放射性的13%、71%、1%和9%。主要代谢产物M2极性很高，在酸性条件下极不稳定，会转化为一种极性较小的产物，鉴定为N - 乙酰基 - 4(S)-羟基 - 4-(4 - 羟基苯基)-L - 苏氨酸γ - 内酯。M2在水性介质中的衍生化导致其被鉴定为相应的γ - 羟基酸，N - 乙酰基 - 4(S)-羟基 - 4-(4 - 羟基苯基)-L - 苏氨酸。代谢产物M1极性极大，从HPLC柱上在空体积后洗脱，通过化学衍生化鉴定为去乙酰基 - M2。因此，MK - 0991的主要尿液和血浆代谢产物是由肽水解和/或N - 乙酰化产生的。
