Tsukimoto Mikiko, Ohashi Rikiya, Torimoto Nao, Togo Yoko, Suzuki Takashi, Maeda Toshio, Kagawa Yoshiyuki
Discovery Screening Center, Mitsubishi Tanabe Pharma Corporation, Toda, Saitama, Japan; Department of Clinical Pharmaceutics, School of Pharmaceutical Sciences, University of Shizuoka, Suruga, Shizuoka, Japan.
Biopharm Drug Dispos. 2015 Jan;36(1):15-33. doi: 10.1002/bdd.1920. Epub 2014 Oct 31.
Aliskiren is a substrate for P-glycoprotein (P-gp) and is metabolized via cytochrome P450 3A4 (CYP3A4). The aim of the present study was to assess whether P-gp influenced the pharmacokinetics of aliskiren and also if drug-drug interactions (DDIs) mediated through P-gp could be reproduced in cynomolgus monkeys. The study investigated the pharmacokinetics of aliskiren in mdr1a/1b gene-deficient (P-gp KO) and wild-type (WT) mice. The area under the plasma concentration-time curve (AUC) following the oral administration of aliskiren was 6.9-fold higher in P-gp KO mice than in WT mice, while no significant differences were observed in the AUC or total plasma clearance following the intravenous administration of aliskiren to P-gp KO mice. Then the pharmacokinetics of aliskiren were evaluated and DDIs between aliskiren and P-gp inhibitors, such as cyclosporin A (CsA) and zosuquidar, examined in cynomolgus monkeys. The AUC for aliskiren were 8.3- and 42.1-fold higher after the oral administration of aliskiren with the concomitant oral administration of zosuquidar and CsA at doses of 10 and 30 mg/kg, respectively. In contrast, the AUC after the intravenous and oral administration of aliskiren was not significantly affected by the oral administration of zosuquidar or intravenous administration of CsA, respectively. These results indicated that P-gp strictly limited the intestinal absorption of aliskiren in mice and monkeys, and also that the effects of intestinal P-gp inhibition by CsA or zosuquidar on the pharmacokinetics of aliskiren were sensitively reproduced in monkeys. In conclusion, aliskiren can be used as a sensitive substrate to evaluate intestinal P-gp inhibition in monkeys.
阿利吉仑是P-糖蛋白（P-gp）的底物，通过细胞色素P450 3A4（CYP3A4）代谢。本研究的目的是评估P-gp是否影响阿利吉仑的药代动力学，以及通过P-gp介导的药物-药物相互作用（DDIs）是否能在食蟹猴中重现。该研究调查了阿利吉仑在多药耐药蛋白1a/1b基因缺陷（P-gp基因敲除，P-gp KO）小鼠和野生型（WT）小鼠中的药代动力学。口服阿利吉仑后，P-gp KO小鼠的血浆浓度-时间曲线下面积（AUC）比WT小鼠高6.9倍，而静脉注射阿利吉仑后，P-gp KO小鼠的AUC或总血浆清除率无显著差异。然后评估了阿利吉仑的药代动力学，并在食蟹猴中研究了阿利吉仑与P-gp抑制剂（如环孢素A（CsA）和唑苏达）之间的DDIs。分别以10和30mg/kg的剂量同时口服唑苏达和CsA后，阿利吉仑的AUC分别高8.3倍和42.1倍。相比之下，口服唑苏达或静脉注射CsA分别对静脉注射和口服阿利吉仑后的AUC无显著影响。这些结果表明，P-gp严格限制了阿利吉仑在小鼠和猴子中的肠道吸收，并且CsA或唑苏达对阿利吉仑药代动力学的肠道P-gp抑制作用在猴子中得到了敏感重现。总之，阿利吉仑可作为评估猴子肠道P-gp抑制作用的敏感底物。
