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.
Footnotes
- Received May 7, 2016.
- Accepted September 14, 2016.
This research was partially supported by the Research on Development of New Drugs project of the Japan Agency for Medical Research and Development.
↵
This article has supplemental material available at dmd.aspetjournals.org.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|