Sandhu Punam, Xu Xin, Bondiskey Peter J, Balani Suresh K, Morris Michael L, Tang Yui S, Miller Alisha R, Pearson Paul G
Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Antimicrob Agents Chemother. 2004 Apr;48(4):1272-80. doi: 10.1128/AAC.48.4.1272-1280.2004.
The metabolism, excretion, and pharmacokinetics of caspofungin (Cancidas; Merck & Co., Inc.) were investigated after administration of a single intravenous dose to mice, rats, rabbits, and monkeys. Caspofungin had a low plasma clearance (0.29 to 1.05 ml/min/kg) and a long terminal elimination half-life (11.7 h to 59.7 h) in all preclinical species. The elimination kinetics of caspofungin were multiphasic and displayed an initial distribution phase followed by a dominant beta-elimination phase. The presence of low levels of prolonged radioactivity in plasma was observed and was partially attributable to the chemical degradation product M0. Excretion studies with [(3)H]caspofungin indicated that the hepatic and renal routes play an important role in the elimination of caspofungin, as a large percentage of the radiolabeled dose was recovered in urine and feces. 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. These results suggest that distribution plays a prominent role in determining the plasma pharmacokinetics and disposition of caspofungin, as very little excretion or biotransformation occurred during the early days after dose administration, a period during which concentrations in plasma fell substantially. The disposition of caspofungin in preclinical species was similar to that reported previously in humans.
对小鼠、大鼠、兔子和猴子单次静脉注射卡泊芬净（ Cancidas；默克公司）后，研究了其代谢、排泄及药代动力学情况。在所有临床前物种中，卡泊芬净的血浆清除率较低（0.29至1.05毫升/分钟/千克），终末消除半衰期较长（11.7小时至59.7小时）。卡泊芬净的消除动力学呈多相，最初为分布相，随后是主要的β消除相。观察到血浆中存在低水平的放射性延长现象，部分归因于化学降解产物M0。用[³H]卡泊芬净进行的排泄研究表明，肝脏和肾脏途径在卡泊芬净的消除中起重要作用，因为放射性标记剂量的很大一部分在尿液和粪便中被回收。在所有研究的物种中，放射性排泄都很缓慢，在延长的收集期内，每日尿液和粪便样本中都检测到低水平的放射性。虽然尿液图谱显示存在几种代谢物（M0、M1、M2、M3、M4、M5和M6），但总放射性的大部分与极性代谢物M1[4(S)-羟基-4-(4-羟基苯基)-L-苏氨酸]和M2[N-乙酰基-4(S)-羟基-4-(4-羟基苯基)-L-苏氨酸]有关。因此，卡泊芬净主要通过代谢转化消除；然而，代谢速率较慢。这些结果表明，分布在决定卡泊芬净的血浆药代动力学和处置方面起主要作用，因为在给药后的早期，血浆浓度大幅下降的这段时间内，排泄或生物转化很少发生。卡泊芬净在临床前物种中的处置情况与先前在人类中报道的相似。
