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Drug Metab Dispos. 2016 Dec;44(12):1925-1933. Epub 2016 Sep 16.

Investigation of Endogenous Compounds Applicable to Drug-Drug Interaction Studies Involving the Renal Organic Anion Transporters, OAT1 and OAT3, in Humans.

Author information

1
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.).
2
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.) kusuhara@mol.f.u-tokyo.ac.jp.

Abstract

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, 6β-hydroxycortisol, taurine, and GCDCA-S). Taurine and GCDCA-S were substrates of OAT1 and OAT3, with Km values of 379 ± 58 and 64.3 ± 3.9 μM, respectively. The Ki 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 CLR of taurine and GCDCA-S by probenecid could be reasonably explained using the geometric mean values of unbound probenecid concentration and Ki 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.

PMID:
27638508
DOI:
10.1124/dmd.116.071472
[Indexed for MEDLINE]

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