Discovery and Validation of Pyridoxic Acid and Homovanillic Acid as Novel Endogenous Plasma Biomarkers of Organic Anion Transporter (OAT) 1 and OAT3 in Cynomolgus Monkeys.

Perturbation of OAT1- and OAT3-mediated transport can alter the exposure, efficacy, and safety of drugs. Although these have been reports of the endogenous biomarkers for OAT1/3, none of these have all of the characteristics required for a clinical useful biomarker. Cynomolgus monkeys were treated with intravenous probenecid (PROB) at a dose of 40 mg/kg in this study. As expected, PROB increased the AUC of co-administered furosemide (FSM), a known substrate of OAT1 and OAT3, by 4.1-fold, consistent with the values reported in humans (3.1- to 3.7-fold). Of 233 plasma metabolites analyzed using a LC-MS/MS-based metabolomics method, 29 metabolites, including pyridoxic acid (PDA) and homovanillic acid (HVA), were significantly increased at either 1 or 3 h in plasma from the monkeys pretreated with PROB compared with the treated animals. Plasma of animals was then subjected to targeted LC-MS/MS analysis which confirmed that the PDA and HVA AUCs increased by approximately 2- to 3-fold by PROB pretreatments. PROB also increased plasma concentrations of hexadecanedioic acid (HDA) and tetradecanedioic acid (TDA) although the increases were not statistically significant. Moreover, transporter profiling assessed using stable cell lines constitutively expressing transporters, demonstrated that PDA and HVA are substrates for human OAT1, OAT3, OAT2 (HVA) and OAT4 (PDA), but not OCT2, MATE1, MATE2K, OATP1B1, OATP1B3, and NTCP. Collectively, these findings suggest that PDA and HVA might serve as blood-based endogenous probes of cynomolgus monkey OAT1 and OAT3, and investigation of PDA and HVA as circulating endogenous biomarkers of human OAT1 and OAT3 function is warranted. The American Society for Pharmacology and Experimental Therapeutics.

Citation

Hong Shen, David M Nelson, Regina V Oliveira, Yueping Zhang, Colleen A Mcnaney, Xiaomei Gu, Weiqi Chen, Ching Su, Michael D Reily, Petia A Shipkova, Jinping Gan, Yurong Lai, Punit Marathe, W Griffith Humphreys. Discovery and Validation of Pyridoxic Acid and Homovanillic Acid as Novel Endogenous Plasma Biomarkers of Organic Anion Transporter (OAT) 1 and OAT3 in Cynomolgus Monkeys. Drug metabolism and disposition: the biological fate of chemicals. 2017 Nov 21

PMID: 29162614

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