Maeda Kazuya, Tian Ying, Fujita Tomoe, Ikeda Yasuhiko, Kumagai Yuji, Kondo Tsunenori, Tanabe Kazunari, Nakayama Hideki, Horita Shigeru, Kusuhara Hiroyuki, Sugiyama Yuichi
Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Clinical Trial Center, Kitasato University East Hospital, 2-1-1 Asamizodai, Minami-ku, Sagamihara City, Kanagawa 252-0380, Japan.
Eur J Pharm Sci. 2014 Aug 1;59:94-103. doi: 10.1016/j.ejps.2014.04.004. Epub 2014 Apr 18.
Probe substrates for, and inhibitors of, specific transporters are desired to evaluate quantitatively the in vivo functions of transporters in humans. Based on published data, adefovir and benzylpenicillin were selected as organic anion transporter (OAT) 1- and OAT3-selective probe substrates, respectively. In human kidney slices, probenecid potently inhibited the uptake of both adefovir and benzylpenicillin with inhibition constant (Ki) values of 18.6±5.1 and 12.6±4.2μM, respectively, whereas p-aminohippurate (PAH) preferentially inhibited adefovir uptake. A clinical drug-interaction study involving healthy subjects was performed to investigate the dose-dependent inhibition potencies of probenecid and PAH on the renal clearance of the probe substrates. Adefovir or benzylpenicillin was coadministered with different oral doses of probenecid (500, 750, or 1500mg) or intravenous PAH infusion rates (70, 120, or 210mg/min/person) to the same subject using a crossover design. The renal clearance of adefovir was reduced by 45% and 46% in the subjects treated with the maximum dose of probenecid and PAH, respectively, which was in accordance with the results of in vitro inhibition study. On the other hand, renal clearance of benzylpenicillin was reduced by 78% in the subjects treated with the maximum dose of probenecid (1500mg), which could be explained by its in vitro Ki values. However, PAH unexpectedly increased the renal clearance of benzylpenicillin by 47%. These results suggest that adefovir and benzylpenicillin can be used as probe drugs for OAT1 and OAT3, respectively, and that PAH can be used to investigate the role of OAT1 in the urinary excretion of drugs in humans, whereas it may modulate other transport processes in the kidney.
为了定量评估转运体在人体中的体内功能，需要特定转运体的探针底物和抑制剂。根据已发表的数据，分别选择阿德福韦和苄青霉素作为有机阴离子转运体（OAT）1和OAT3的选择性探针底物。在人肾切片中，丙磺舒强烈抑制阿德福韦和苄青霉素的摄取，抑制常数（Ki）值分别为18.6±5.1和l2.6±4.2μM，而对氨基马尿酸（PAH）优先抑制阿德福韦的摄取。进行了一项涉及健康受试者的临床药物相互作用研究，以研究丙磺舒和PAH对探针底物肾清除率的剂量依赖性抑制效力。使用交叉设计，将阿德福韦或苄青霉素与不同口服剂量的丙磺舒（500、750或1500mg）或静脉注射PAH输注速率（70、120或210mg/分钟/人）共同给予同一受试者。在接受最大剂量丙磺舒和PAH治疗的受试者中，阿德福韦的肾清除率分别降低了45%和46%，这与体外抑制研究的结果一致。另一方面，在接受最大剂量丙磺舒（1500mg）治疗的受试者中，苄青霉素的肾清除率降低了78%，这可以用其体外Ki值来解释。然而，PAH意外地使苄青霉素的肾清除率提高了47%。这些结果表明，阿德福韦和苄青霉素可分别用作OAT1和OAT3的探针药物，并且PAH可用于研究OAT1在人体药物尿排泄中的作用，而它可能调节肾脏中的其他转运过程。
