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

Drug Metab Dispos. 2016 Dec;44(12):1925-1933. doi: 10.1124/dmd.116.071472. Epub 2016 Sep 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cell Line
  • Drug Interactions / physiology*
  • HEK293 Cells
  • Humans
  • Hydrocortisone / analogs & derivatives
  • Hydrocortisone / metabolism
  • Hydrocortisone / pharmacology
  • Kidney / drug effects
  • Kidney / metabolism*
  • Male
  • Organic Anion Transport Protein 1 / metabolism*
  • Organic Anion Transporters, Sodium-Independent / metabolism*
  • Penicillin G / metabolism
  • Penicillin G / pharmacology
  • Probenecid / metabolism*
  • Probenecid / pharmacology
  • Taurine / metabolism
  • Taurine / pharmacology
  • Young Adult


  • Organic Anion Transport Protein 1
  • Organic Anion Transporters, Sodium-Independent
  • organic anion transport protein 3
  • Taurine
  • 6 beta-hydroxycortisol
  • Probenecid
  • Penicillin G
  • Hydrocortisone