Mangold J B, Schran H F, Tse F L
Drug Metabolism and Pharmacokinetics Department, Sandoz Research Institute, Sandoz Pharmaceuticals Corporation, East Hanover, NJ 07936.
Drug Metab Dispos. 1994 Nov-Dec;22(6):873-9.
The pharmacokinetics and metabolism of cyclosporin G (CsG; Sandoz compound OG 37-325) were studied in 12 healthy male volunteers receiving a single oral dose of 150 or 600 mg of [14C]CsG. Serial blood and plasma samples and complete urine and feces were collected for 120-hr postdose. CsG was rapidly absorbed, and the extent of absorption was dose-independent. Maximum blood concentrations of CsG at 2- to 3-hr postdose averaged 342 and 1170 ng/ml after doses of 150 and 600 mg, respectively, each accounting for approximately 50% of the blood radioactivity level. The plasma:blood concentration ratio for both CsG and total radioactivity averaged approximately 0.8. Overall disposition of absorbed CsG was independent of the dose. The drug was extensively metabolized with excretion predominantly via the fecal route. Total recovery in urine was only approximately 3% of the dose. In blood, the terminal half-life of CsG and total radioactivity averaged 9-11 hr following both the 150 and 600 mg doses. In plasma, the half-life of CsG was 2-4 hr and that of total radioactivity was 27-29 hr. The major metabolic pathways resulted from oxidative modifications at amino acids 1, 4, and 9, with concomitant cyclization of amino acid 1 in two metabolites. These pathways resulted in formation of seven major metabolites (designated GM19, GM1c9, GM4N9, GM1, GM9, GM1c, and GM4N) observed in human excreta and/or blood. Major metabolites of CsG in blood involved monohydroxylation (GM1 and GM9) or demethylation (GM4N). In blood, monohydroxylated CsG metabolites (GM1 and GM9) achieved roughly equal levels, with a trend toward higher GM9 concentrations at peak radioactivity.
在12名健康男性志愿者中进行了研究，这些志愿者单次口服150或600毫克[14C]环孢菌素G（CsG；山德士化合物OG 37 - 325），以考察其药代动力学和代谢情况。给药后120小时内收集系列血液和血浆样本以及完整的尿液和粪便。CsG吸收迅速，吸收程度与剂量无关。给药后2至3小时，CsG的最大血药浓度在150毫克和600毫克剂量后分别平均为342和1170纳克/毫升，各占血放射性水平的约50%。CsG和总放射性的血浆与血液浓度比平均约为0.8。吸收的CsG的总体处置与剂量无关。该药物被广泛代谢，主要通过粪便途径排泄。尿液中的总回收率仅约为给药剂量的3%。在血液中，150毫克和600毫克剂量后CsG和总放射性的末端半衰期平均为9至11小时。在血浆中，CsG的半衰期为2至4小时，总放射性的半衰期为27至29小时。主要代谢途径是由氨基酸1、4和9处的氧化修饰导致的，同时氨基酸1在两种代谢物中伴随环化。这些途径导致在人体排泄物和/或血液中观察到七种主要代谢物（分别命名为GM19、GM1c9、GM4N9、GM1、GM9、GM1c和GM4N）。血液中CsG的主要代谢物涉及单羟基化（GM1和GM9）或去甲基化（GM4N）。在血液中，单羟基化的CsG代谢物（GM1和GM9）达到大致相等的水平，在放射性峰值时GM9浓度有升高趋势。
