Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects
Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects
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DOI：
10.1177/0091270006296523
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发表时间：
2007-02-01
影响因子：
2.9
通讯作者：
Herman, Gary
中科院分区：
文献类型：
--
作者：
Krishna, Rajesh;Bergman, Arthur;Herman, Gary
西格列汀（MK-0431）是一种口服活性、强效和选择性二肽基肽酶-4抑制剂，用于治疗2型糖尿病患者。在临床前研究中，西格列汀已被证明是P-糖蛋白的底物。在健康男性受试者中，使用高剂量环孢素作为探针P-糖蛋白抑制剂，以评价强效P-糖蛋白抑制对单次给药西格列汀药代动力学的潜在影响。在一项开放标签、随机、2阶段、交叉研究中，8名健康年轻男性接受单次口服600 mg环孢素联合单次口服100 mg西格列汀和单次口服100 mg西格列汀。西格列汀单次给药伴或不伴环孢菌素单次给药通常耐受良好。西格列汀AUC（0-无穷大）几何均值比为1.29，90%置信区间为（1.24，1.34）。西格列汀C-max几何均值比为1.68，90%置信区间为（1.35，2.08）。环孢素联合给药似乎不影响西格列汀的表观肾脏清除率、t（1/2）或C-24 h，表明这些高剂量环孢素的作用更可能是由于西格列汀的吸收增强，可能通过抑制肠道P-糖蛋白。这些结果合理使用单一高剂量环孢素作为P-糖蛋白的探针抑制剂的化合物候选人，其消除是较少依赖于CYP 3A 4介导的代谢。
Sitagliptin (MK-0431) is an orally active, potent, and selective dipeptidyl peptidase-4 inhibitor used for the treatment of patients with type 2 diabetes mellitus. Sitagliptin has been shown to be a substrate for P-glycoprotein in preclinical studies. Cyclosporine was used as a probe P-glycoprotein inhibitor at a high dose to evaluate the potential effect of potent P-glycoprotein inhibition on single-dose sitagliptin pharmacokinetics in healthy male subjects. Eight healthy young men received a single oral 600-mg dose of cyclosporine with a single 100-mg oral sitagliptin dose and a single oral 100-mg sitagliptin dose alone in an open-label, randomized, 2-period, crossover study. Single doses of sitagliptin with or without single doses of cyclosporine were generally well tolerated. The sitagliptin AUC(0-infinity) geometric mean ratio was 1.29 with a 90% confidence interval of (1.24, 1.34). The sitagliptin C-max geometric mean ratio was 1.68 with a 90% confidence interval of (1.35, 2.08). Cyclosporine coadministration did not appear to affect apparent sitagliptin renal clearance, t(1/2), or C-24h, suggesting that effects of these high doses of cyclosporine are more likely due to enhanced absorption of sitagliptin, potentially through inhibition of intestinal P-glycoprotein. These results rationalize the use of a single high-dose cyclosporine as a probe inhibitor of P-glycoprotein for compound candidates whose elimination is less dependent on CYP3A4-mediated metabolism.