Tsuruya Yuri, Kato Koji, Sano Yamato, Imamura Yuichiro, Maeda Kazuya, Kumagai Yuji, Sugiyama Yuichi, Kusuhara Hiroyuki
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.T., Y.Sa., K.M., H.K.); Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan (K.K.); Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Tokyo, Japan (Y.I.); Clinical Trial Center, Kitasato University Hospital, Kanagawa, Japan (Y.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.Su.).
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.T., Y.Sa., K.M., H.K.); Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan (K.K.); Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Tokyo, Japan (Y.I.); Clinical Trial Center, Kitasato University Hospital, Kanagawa, Japan (Y.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.Su.)
Drug Metab Dispos. 2016 Dec;44(12):1925-1933. doi: 10.1124/dmd.116.071472. Epub 2016 Sep 16.
This study was a comprehensive analysis of metabolites in plasma and urine specimens from subjects who received probenecid, a potent inhibitor of renal organic anion transporters (OATs). Taurine and glycochenodeoxycholate sulfate (GCDCA-S) could be identified using authentic standards. Probenecid had no effect on the area under the plasma-concentration time curves of taurine and GCDCA-S, whereas it significantly inhibited their urinary excretion in a dose-dependent manner. Probenecid at 500, 750, and 1500 mg orally decreased the renal clearance (CL) values of taurine and GCDCA-S by 45% and 60%, 59% and 79%, and 70% and 88%, respectively. The CL values correlated strongly (r > 0.96) between the test compounds (benzylpenicillin, 6β-hydroxycortisol, taurine, and GCDCA-S). Taurine and GCDCA-S were substrates of OAT1 and OAT3, with K values of 379 ± 58 and 64.3 ± 3.9 μM, respectively. The K values of probenecid for the OAT1- and OAT3-mediated uptake of taurine and GCDCA-S (9.49 ± 1.27 and 7.40 ± 0.70 μM, respectively) were similar to those of their typical substrate drugs. The magnitude of the reduction in the CL of taurine and GCDCA-S by probenecid could be reasonably explained using the geometric mean values of unbound probenecid concentration and K values. These results suggest that taurine and GCDCA-S can be used as probes for evaluating pharmacokinetic drug-drug interactions involving OAT1 and OAT3, respectively, in humans.
本研究对接受丙磺舒（一种强效肾有机阴离子转运体（OATs）抑制剂）的受试者的血浆和尿液样本中的代谢物进行了全面分析。使用标准品可鉴定出牛磺酸和甘氨鹅脱氧胆酸硫酸盐（GCDCA-S）。丙磺舒对牛磺酸和GCDCA-S的血浆浓度-时间曲线下面积无影响，但其以剂量依赖性方式显著抑制它们的尿排泄。口服500、750和1500mg丙磺舒分别使牛磺酸和GCDCA-S的肾清除率（CL）值降低45%和60%、59%和79%、70%和88%。测试化合物（苄青霉素、6β-羟基皮质醇、牛磺酸和GCDCA-S）之间的CL值相关性很强（r>0.96）。牛磺酸和GCDCA-S是OAT1和OAT3的底物，K值分别为379±58和64.3±3.9μM。丙磺舒对OAT1和OAT3介导的牛磺酸和GCDCA-S摄取的K值（分别为9.49±1.27和7.40±0.70μM）与其典型底物药物的K值相似。使用未结合丙磺舒浓度和K值的几何平均值可以合理解释丙磺舒对牛磺酸和GCDCA-S的CL降低幅度。这些结果表明，牛磺酸和GCDCA-S可分别用作评估人体中涉及OAT1和OAT3的药代动力学药物-药物相互作用的探针。
