Evidence for the Validity of Pyridoxic Acid (PDA) as a Plasma-Based Endogenous Probe for OAT1 and OAT3 Function in Healthy Subjects.

Autor: Shen H; Metabolism and Pharmacokinetics Department (H.S., Y.Z., J.G., P.M., W.G.H.) and Bioanalytical and Discovery Analytical Sciences Department (P.A.S.), Bristol-Myers Squibb Company, Princeton, New Jersey; Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bangalore, India (V.K.H., T.T.M., P.R., S.S.G.); and Bioanalytical and Discovery Analytical Sciences Department, Bristol-Myers Squibb Company, Wallingford, Connecticut (D.M.D., J.L.C.) hong.shen1@bms.com., Holenarsipur VK; Metabolism and Pharmacokinetics Department (H.S., Y.Z., J.G., P.M., W.G.H.) and Bioanalytical and Discovery Analytical Sciences Department (P.A.S.), Bristol-Myers Squibb Company, Princeton, New Jersey; Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bangalore, India (V.K.H., T.T.M., P.R., S.S.G.); and Bioanalytical and Discovery Analytical Sciences Department, Bristol-Myers Squibb Company, Wallingford, Connecticut (D.M.D., J.L.C.)., Mariappan TT; Metabolism and Pharmacokinetics Department (H.S., Y.Z., J.G., P.M., W.G.H.) and Bioanalytical and Discovery Analytical Sciences Department (P.A.S.), Bristol-Myers Squibb Company, Princeton, New Jersey; Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bangalore, India (V.K.H., T.T.M., P.R., S.S.G.); and Bioanalytical and Discovery Analytical Sciences Department, Bristol-Myers Squibb Company, Wallingford, Connecticut (D.M.D., J.L.C.)., Drexler DM; Metabolism and Pharmacokinetics Department (H.S., Y.Z., J.G., P.M., W.G.H.) and Bioanalytical and Discovery Analytical Sciences Department (P.A.S.), Bristol-Myers Squibb Company, Princeton, New Jersey; Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bangalore, India (V.K.H., T.T.M., P.R., S.S.G.); and Bioanalytical and Discovery Analytical Sciences Department, Bristol-Myers Squibb Company, Wallingford, Connecticut (D.M.D., J.L.C.)., Cantone JL; Metabolism and Pharmacokinetics Department (H.S., Y.Z., J.G., P.M., W.G.H.) and Bioanalytical and Discovery Analytical Sciences Department (P.A.S.), Bristol-Myers Squibb Company, Princeton, New Jersey; Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bangalore, India (V.K.H., T.T.M., P.R., S.S.G.); and Bioanalytical and Discovery Analytical Sciences Department, Bristol-Myers Squibb Company, Wallingford, Connecticut (D.M.D., J.L.C.)., Rajanna P; Metabolism and Pharmacokinetics Department (H.S., Y.Z., J.G., P.M., W.G.H.) and Bioanalytical and Discovery Analytical Sciences Department (P.A.S.), Bristol-Myers Squibb Company, Princeton, New Jersey; Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bangalore, India (V.K.H., T.T.M., P.R., S.S.G.); and Bioanalytical and Discovery Analytical Sciences Department, Bristol-Myers Squibb Company, Wallingford, Connecticut (D.M.D., J.L.C.)., Singh Gautam S; Metabolism and Pharmacokinetics Department (H.S., Y.Z., J.G., P.M., W.G.H.) and Bioanalytical and Discovery Analytical Sciences Department (P.A.S.), Bristol-Myers Squibb Company, Princeton, New Jersey; Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bangalore, India (V.K.H., T.T.M., P.R., S.S.G.); and Bioanalytical and Discovery Analytical Sciences Department, Bristol-Myers Squibb Company, Wallingford, Connecticut (D.M.D., J.L.C.)., Zhang Y; Metabolism and Pharmacokinetics Department (H.S., Y.Z., J.G., P.M., W.G.H.) and Bioanalytical and Discovery Analytical Sciences Department (P.A.S.), Bristol-Myers Squibb Company, Princeton, New Jersey; Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bangalore, India (V.K.H., T.T.M., P.R., S.S.G.); and Bioanalytical and Discovery Analytical Sciences Department, Bristol-Myers Squibb Company, Wallingford, Connecticut (D.M.D., J.L.C.)., Gan J; Metabolism and Pharmacokinetics Department (H.S., Y.Z., J.G., P.M., W.G.H.) and Bioanalytical and Discovery Analytical Sciences Department (P.A.S.), Bristol-Myers Squibb Company, Princeton, New Jersey; Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bangalore, India (V.K.H., T.T.M., P.R., S.S.G.); and Bioanalytical and Discovery Analytical Sciences Department, Bristol-Myers Squibb Company, Wallingford, Connecticut (D.M.D., J.L.C.)., Shipkova PA; Metabolism and Pharmacokinetics Department (H.S., Y.Z., J.G., P.M., W.G.H.) and Bioanalytical and Discovery Analytical Sciences Department (P.A.S.), Bristol-Myers Squibb Company, Princeton, New Jersey; Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bangalore, India (V.K.H., T.T.M., P.R., S.S.G.); and Bioanalytical and Discovery Analytical Sciences Department, Bristol-Myers Squibb Company, Wallingford, Connecticut (D.M.D., J.L.C.)., Marathe P; Metabolism and Pharmacokinetics Department (H.S., Y.Z., J.G., P.M., W.G.H.) and Bioanalytical and Discovery Analytical Sciences Department (P.A.S.), Bristol-Myers Squibb Company, Princeton, New Jersey; Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bangalore, India (V.K.H., T.T.M., P.R., S.S.G.); and Bioanalytical and Discovery Analytical Sciences Department, Bristol-Myers Squibb Company, Wallingford, Connecticut (D.M.D., J.L.C.)., Humphreys WG; Metabolism and Pharmacokinetics Department (H.S., Y.Z., J.G., P.M., W.G.H.) and Bioanalytical and Discovery Analytical Sciences Department (P.A.S.), Bristol-Myers Squibb Company, Princeton, New Jersey; Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bangalore, India (V.K.H., T.T.M., P.R., S.S.G.); and Bioanalytical and Discovery Analytical Sciences Department, Bristol-Myers Squibb Company, Wallingford, Connecticut (D.M.D., J.L.C.).
Jazyk: angličtina
Zdroj: The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2019 Jan; Vol. 368 (1), pp. 136-145. Date of Electronic Publication: 2018 Oct 25.
DOI: 10.1124/jpet.118.252643
Abstrakt: 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 ( CL R ) 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 CL R values between subjects is more favorable relative to HVA.
(Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze: MEDLINE
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