6β-Hydroxycortisol Is an Endogenous Probe for Evaluation of Drug-Drug Interactions Involving a Multispecific Renal Organic Anion Transporter, OAT3/SLC22A8, in Healthy Subjects
6β-Hydroxycortisol Is an Endogenous Probe for Evaluation of Drug-Drug Interactions Involving a Multispecific Renal Organic Anion Transporter, OAT3/SLC22A8, in Healthy Subjects
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DOI：
10.1124/dmd.113.055475
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发表时间：
2014-04-01
影响因子：
3.9
通讯作者：
Kusuhara, Hiroyuki
中科院分区：
文献类型：
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作者：
Imamura, Yuichiro;Tsuruya, Yuri;Kusuhara, Hiroyuki
6 β-羟基皮质醇（6 β-OHF）是相应cDNA转染细胞中有机阴离子转运蛋白3（OAT 3）以及多药和毒素外排蛋白MATE 1和MATE-2K的底物。本研究旨在使用适当的OAT 3和MATE体内抑制剂丙磺舒和乙胺嘧啶分别检查OAT 3和MATE对人体6 β-OHF尿液排泄的贡献。与野生型小鼠相比，Oat 3（-/-）小鼠显示6 β-OHF（CL renal，（6 β-OHF））的肾脏清除率显著降低（18.1 +/-1.5 vs 7.60 +/-1.8 ml/min/kg）。丙磺舒可显著抑制人肾片对6 β-OHF的摄取，抑制率为对照值的20 - 45%，1-甲基-4-苯基吡啶可部分抑制。在参加药物相互作用研究的健康受试者中测量6 β-OHF血浆浓度和排泄到尿液中的6 β-OHF的量（X6 β-OHF），所述药物相互作用研究包括苄青霉素单独或与丙磺舒（研究1）、阿德福韦单独或与丙磺舒（研究2）以及二甲双胍单独或与乙胺嘧啶（研究3）。丙磺舒治疗导致研究1和2中6 β-OHF的血浆浓度-时间曲线下面积（AUC（6 β-OHF））分别增加57%和76%，但不影响X6 β-OHF。因此，在研究1和2中丙磺舒给药后，CL肾，6 β-OHF（毫升/分钟）分别从231 +/-11显著降低至135 +/-9和从225 +/-26显著降低至141 +/-12。相比之下，乙胺嘧啶给药后AUC（6 β-OHF）和CL renal，6 β-OHF均未发生显著变化。总之，这些数据表明OAT 3在6 β-OHF的尿排泄中起重要作用，并且6 β-OHF可用于研究人体中涉及OAT 3的药代动力学药物相互作用的肇事者。
6 beta-Hydroxycortisol (6 beta-OHF) is a substrate of the organic anion transporter 3 (OAT3) and the multidrug and toxin extrusion proteins MATE1 and MATE-2K in the corresponding cDNA-transfected cells. This study aimed to examine the contribution of OAT3 and MATEs to the urinary excretion of 6 beta-OHF in humans using the appropriate in vivo inhibitors, probenecid and pyrimethamine, for OAT3 and MATEs, respectively. Oat3(-/-) mice showed significantly reduced renal clearance of 6 beta-OHF (CLrenal, (6 beta-OHF)) compared with wild-type mice (18.1 +/- 1.5 versus 7.60 +/- 1.8 ml/min/kg). 6 beta-OHF uptake by human kidney slices was inhibited significantly by probenecid to 20-45% of the control values and partly by 1-methyl-4-phenylpyridinium. 6 beta-OHF plasma concentration and the amount of 6 beta-OHF excreted into the urine (X6 beta-OHF) were measured in healthy subjects enrolled in drug-drug interaction studies of benzylpenicillin alone or with probenecid (study 1), adefovir alone or with probenecid (study 2), and metformin alone or with pyrimethamine (study 3). Probenecid treatment caused a 57 and 76% increase in the area under the plasma concentration-time curve for 6 beta-OHF (AUC(6 beta-OHF)) in studies 1 and 2, respectively, but did not affect X6 beta-OHF. Consequently, CLrenal, 6 beta-OHF (milliliters per minute) decreased significantly from 231 +/- 11 to 135 +/- 9 and from 225 +/- 26 to 141 +/- 12 after probenecid administration in studies 1 and 2, respectively. By contrast, neither AUC(6 beta-OHF) nor CLrenal, 6 beta-OHF was significantly altered by pyrimethamine administration. Taken together, these data suggest that OAT3 plays a significant role in the urinary excretion of 6 beta-OHF, and that 6 beta-OHF can be used to investigate the perpetrators of the pharmacokinetic drug interactions involving OAT3 in humans.