In vitro transporter substrate properties of previously reported biomarkers for renal OAT1/OAT3-mediated drug-drug interactions

Organic anion transporters (OAT) 1 and 3 are important for renal drug elimination. Assessment of the potential to cause transporter-mediated drug-drug interactions (DDI) is required during drug development. Clinical readouts could be improved by using endogenous biomarkers for transporter-mediated DDI. There is still a need for well-characterized, sensitive and specific biomarkers. From previous metabolomic studies in healthy volunteers, seven sensitive and specific potential biomarkers for OAT1/OAT3-mediated renal DDI were selected, which remained insufficiently characterized as substrates of OAT1, OAT3 and other drug transporters in vitro: indolelactic acid, cinnamoylglycine, indoleacetyl glutamine, phenylacetylglutamine, 1,7-dimethyluric acid, 1-methyluric acid and 7-methyluric acid. Therefore, we used cell models to characterize transport properties regarding OAT1, OAT3, organic anion transporting polypeptides 1B1 and 1B3, organic cation transporter 2, multidrug and toxin extrusion protein 1 and P-glycoprotein, together with OAT1/OAT3 transport kinetics for two most promising candidates. All seven potential biomarkers were identified as substrates of OAT1 and OAT3 (K_m of indolelactic acid and indoleacetyl glutamine for OAT1: 319.4 ± 31.9 µM and 609.8 ± 129.2 µM, respectively; and for OAT3: 290.1 ± 41.0 µM and 161.4 ± 20.3 µM, respectively), while transport by other transporters was completely absent or low compared to OAT1/OAT3-mediated uptake. Altogether, based on the consistency of present in vitro and previous in vivo results and the possible impact of diet on disposition of the investigated potential biomarkers, indolelactic acid and indoleacetyl glutamine emerge as the most promising candidates for further validation as biomarkers for OAT1/OAT3-mediated renal drug-drug interactions.