RT Journal Article
SR Electronic
T1 Evidence for the Validity of Pyridoxic Acid (PDA) as a Plasma-Based Endogenous Probe for OAT1 and OAT3 Function in Healthy Subjects
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 136
OP 145
DO 10.1124/jpet.118.252643
VO 368
IS 1
A1 Hong Shen
A1 Vinay K. Holenarsipur
A1 T. Thanga Mariappan
A1 Dieter M. Drexler
A1 Joseph L. Cantone
A1 Prabhakar Rajanna
A1 Shashyendra Singh Gautam
A1 Yueping Zhang
A1 Jinping Gan
A1 Petia A. Shipkova
A1 Punit Marathe
A1 W. Griffith Humphreys
YR 2019
UL http://jpet.aspetjournals.org/content/368/1/136.abstract
AB Plasma pyridoxic acid (PDA) and homovanillic acid (HVA) were recently identified as novel endogenous biomarkers of organic anion transporter (OAT) 1/3 function in monkeys. Consequently, this clinical study assessed the dynamic changes and utility of plasma PDA and HVA as an initial evaluation of OAT1/3 inhibition in early-phase drug development. The study was designed as a single-dose randomized, three-phase, crossover study; 14 Indian healthy volunteers received probenecid (PROB) (1000 mg orally) alone, furosemide (FSM) (40 mg orally) alone, or FSM 1 hour after receiving PROB (40 and 1000 mg orally) on days 1, 8, and 15, respectively. PDA and HVA plasma concentrations remained stable over time in the prestudy and FSM groups. Administration of PROB significantly increased the area under the plasma concentration-time curve (AUC) of PDA by 3.1-fold (dosed alone; P < 0.05), and 3.2-fold (coadministered with FSM; P < 0.01), compared with the prestudy and FSM groups, respectively. The corresponding increase in HVA AUC was 1.8-fold (P > 0.05) and 2.1-fold (P < 0.05), respectively. The increases in PDA AUC are similar to those in FSM AUC, whereas those of HVA are smaller (3.1–3.2 and 1.8–2.1 vs. 3.3, respectively). PDA and HVA renal clearance (CLR) values were decreased by PROB to smaller extents compared with FSM (0.35–0.37 and 0.67–0.73 vs. 0.23, respectively). These data demonstrate that plasma PDA is a promising endogenous biomarker for OAT1/3 function and that its plasma exposure responds in a similar fashion to FSM upon OAT1/3 inhibition by PROB. The magnitude and variability of response in PDA AUC and CLR values between subjects is more favorable relative to HVA.