Journal
DRUG METABOLISM AND DISPOSITION
Volume 44, Issue 12, Pages 1925-1933Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/dmd.116.071472
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Funding
- Research on Development of New Drugs project of the Japan Agency for Medical Research and Development
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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.
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