TY - JOUR T1 - Endogenous plasma kynurenic acid in human: a newly discovered biomarker for drug-drug interactions involving in OAT1 and OAT3 inhibition JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.121.000486 SP - DMD-AR-2021-000486 AU - Jennifer Tang AU - Hong Shen AU - Xiaofeng Zhao AU - Vinay K. Holenarsipur AU - T. Thanga Mariappan AU - Yueping Zhang AU - Erika Panfen AU - Jim Zheng AU - W. Griffith Humphreys AU - Yurong Lai Y1 - 2021/01/01 UR - http://dmd.aspetjournals.org/content/early/2021/10/01/dmd.121.000486.abstract N2 - As an expansion investigation of drug-drug interaction (DDI) from previous clinical trials (Shen et al., 2019), additional plasma endogenous metabolites were quantitated in the same subjects to further identify the potential biomarkers of OAT1/3 inhibition. In the single dose, open label, three-phase with fixed order of treatments study, 14 healthy human volunteers orally received 1000 mg probenecid alone, or 40 mg furosemide alone, or 40 mg furosemide at 1 h after receiving 1000 mg probenecid on Days 1, 8, and 15, respectively. Endogenous metabolites including kynurenic acid, xanthurenic acid, indo-3-acetic acid, pantothenic acid, p-cresol sulfate, and bile acids in the plasma were measured by LC-MS/MS. The Cmax of kynurenic acids was significantly increased about 3.3- and 3.7-fold over the baseline values at pre-dose followed by the treatment of probenecid alone or in combination with furosemide respectively. In comparison with the furosemide alone group, the Cmax and AUC0-12 of kynurenic acid were significantly increased about 2.4 and 2.5-fold by probenecid alone, and 2.7 and 2.9-fold by probenecid plus furosemide, respectively. The increases in Cmax and AUC of plasma kynurenic acid by probenecid are comparable to the increases of furosemide Cmax and AUC reported previously. Additionally, the plasma concentrations of xanthurenic acid, indo-3-acetic acid, pantothenic acid, and p-cresol sulfate, but not bile acids, were also significantly elevated by probenecid treatments. The magnitude of effect size analysis for known potential endogenous biomarkers demonstrated that kynurenic acid in the plasma offers promise as a superior addition for early DDI assessment involving OAT1/3 inhibition. Significance Statement We reported that probenecid, an OAT1 and OAT3 inhibitor, significantly increased the plasma concentrations of kynurenic acid and several uremic acids in human subjects. Of those, the increases of plasma kynurenic acid exposure are comparable to the increases of furosemide by OAT1/3 inhibition. Effect size analysis for known potential endogenous biomarkers revealed that plasma kynurenic acid is a superior addition for early DDI assessment involving OAT1/3 inhibition. ER -