PT  - JOURNAL ARTICLE
AU  - Yuri Tsuruya
AU  - Koji Kato
AU  - Yamato Sano
AU  - Yuichiro Imamura
AU  - Kazuya Maeda
AU  - Yuji Kumagai
AU  - Yuichi Sugiyama
AU  - Hiroyuki Kusuhara
TI  - Investigation of Endogenous Compounds Applicable to Drug–Drug Interaction Studies Involving the Renal Organic Anion Transporters, OAT1 and OAT3, in Humans
AID  - 10.1124/dmd.116.071472
DP  - 2016 Dec 01
TA  - Drug Metabolism and Disposition
PG  - 1925--1933
VI  - 44
IP  - 12
4099  - http://dmd.aspetjournals.org/content/44/12/1925.short
4100  - http://dmd.aspetjournals.org/content/44/12/1925.full
SO  - Drug Metab Dispos2016 Dec 01; 44
AB  - 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.