Slowly metabolized by hydrolysis and N-acetylation; also undergoes spontaneous chemical degradation and further hydrolysis to constitutive amino acids and their degredates, including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine.
Caspofungin is slowly metabolized in the liver via hydrolysis and N-acetylation; 35 and 41% of the parent drug and metabolites were excreted in feces and urine, respectively, following a single IV radiolabeled dose.
The metabolism, excretion, and pharmacokinetics of caspofungin were investigated after administration of a single intravenous dose to mice, rats, rabbits, and monkeys. ... Excretion of radioactivity in all species studied was slow, and low levels of radioactivity were detected in daily urine and fecal samples throughout a prolonged collection period. Although urinary profiles indicated the presence of several metabolites (M0, M1, M2, M3, M4, M5, and M6), the majority of the total radioactivity was associated with the polar metabolites M1 [4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine] and M2 (N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine). Caspofungin was thus primarily eliminated by metabolic transformation; however, the rate of metabolism was slow. ...
Caspofungin is slowly metabolized by hydrolysis and N-acetylation. Caspofungin also undergoes spontaneous chemical degradation to an open-ring peptide compound, L-747969. At later time points (> or = 5 days postdose), there is a low level (< or = 7 picomoles/mg protein, or < or = 1.3% of administered dose) of covalent binding of radiolabel in plasma following single-dose administration of (3)H caspofungin acetate, which may be due to two reactive intermediates formed during the chemical degradation of caspofungin to L-747969. Additional metabolism involves hydrolysis into constitutive amino acids and their degradates, including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine. These two tyrosine derivatives are found only in urine, suggesting rapid clearance of these derivatives by the kidneys. /Caspofungin acetate/
... Following a 1 hr IV infusion of 70 mg of (3)HCaspofungin acetate 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 hr postdose contained predominantly unchanged caspofungin acetate, 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. /Caspofungin acetate/
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 用于研究药物诱导肝损伤的FDA批准药物标签，药物发现今日，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按在人类中发展药物诱导肝损伤风险排名的最大参考药物清单。药物发现今日2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
Elimination: Fecal: 35% as drug or metabolites. Renal: 41% as drug (approximately 1.4% unchanged) or metabolites. In dialysis: Not removed by hemodialysis.
Following administration of a single 70 mg irradiated dose, approximately 92% of the administered radioactivity was distributed into tissues within 36 to 48 hours. Distribution into red blood cells in minimal.
