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首页> 外文期刊>Drug Metabolism and Disposition: The Biological Fate of Chemicals >Investigation of Endogenous Compounds Applicable to Drug-Drug Interaction Studies Involving the Renal Organic Anion Transporters, OAT1 and OAT3, in Humans
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Investigation of Endogenous Compounds Applicable to Drug-Drug Interaction Studies Involving the Renal Organic Anion Transporters, OAT1 and OAT3, in Humans

机译：适用于涉及人类肾脏有机阴离子转运蛋白OAT1和OAT3的药物相互作用研究的内源性化合物的研究

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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 (CLR) values of taurine and GCDCA-S by 45% and 60%, 59% and 79%, and 70% and 88%, respectively. The CLR values correlated strongly (r > 0.96) between the test compounds (benzylpenicillin, 6 beta-hydroxycortisol, taurine, and GCDCA-S). Taurine and GCDCA-S were substrates of OAT1 and OAT3, with K-m values of 379 +/- 58 and 64.3 +/- 3.9 mu M, respectively. The K-i values of probenecid for the OAT1- and OAT3-mediated uptake of taurine and GCDCA-S (9.49 +/- 1.27 and 7.40 +/- 0.70 mu M, respectively) were similar to those of their typical substrate drugs. The magnitude of the reduction in the CLR of taurine and GCDCA-S by probenecid could be reasonably explained using the geometric mean values of unbound probenecid concentration and K-i 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.
机译：这项研究是对接受丙磺舒（一种有效的肾有机阴离子转运蛋白（OAT）抑制剂）的受试者血浆和尿液样本中代谢物的综合分析。牛磺酸和硫酸葡萄糖醛脱氧胆酸盐（GCDCA-S）可以使用可靠的标准品进行鉴定。丙磺舒对牛磺酸和GCDCA-S的血浆浓度时间曲线下的面积没有影响，而以剂量依赖的方式显着抑制了它们的尿排泄。口服丙磺舒500、750和1500 mg会使牛磺酸和GCDCA-S的肾清除率（CLR）值分别降低45％和60％，59％和79％，70％和88％。测试化合物（苄青霉素，6-β-羟基皮质醇，牛磺酸和GCDCA-S）之间的CLR值密切相关（r> 0.96）。牛磺酸和GCDCA-S是OAT1和OAT3的底物，K-m值分别为379 +/- 58和64.3 +/- 3.9μM。 OAT1和OAT3介导的牛磺酸和GCDCA-S摄取的丙磺舒的K-i值（分别为9.49 +/- 1.27和7.40 +/- 0.70μM）类似于其典型的底物药物。丙磺舒对牛磺酸和GCDCA-S的CLR降低的幅度可以使用未结合的丙磺舒浓度的几何平均值和K-i值合理解释。这些结果表明，牛磺酸和GCDCA-S可以用作评估人中涉及OAT1和OAT3的药代动力学药物-药物相互作用的探针。

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