Picurová Jana, Gessner Arne, Bartels Nora, Scheuerlein Sofie, Fischer Oliver, Lochschmidt Lena, Wenisch Pia, Stopfer Peter, Heinrich Markus R, König Jörg, Fromm Martin F
Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; FAU NeW - Research Center New Bioactive Compounds, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Biochem Pharmacol. 2025 Nov;241:117184. doi: 10.1016/j.bcp.2025.117184. Epub 2025 Jul 19.
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 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.
有机阴离子转运体（OAT）1和3对肾脏药物消除至关重要。在药物研发过程中，需要评估引起转运体介导的药物相互作用（DDI）的可能性。使用内源性生物标志物来评估转运体介导的DDI，可能会改善临床结果。目前仍需要特征明确、灵敏且特异的生物标志物。从之前针对健康志愿者的代谢组学研究中，筛选出了7种灵敏且特异的、可能作为OAT1/OAT3介导的肾脏DDI生物标志物的物质，但它们作为OAT1、OAT3及其他药物转运体的底物，在体外的特征仍不够明确，这些物质分别是：吲哚乳酸、肉桂酰甘氨酸、吲哚乙酰谷氨酰胺、苯乙酰谷氨酰胺、1,7-二甲基尿酸、1-甲基尿酸和7-甲基尿酸。因此，我们利用细胞模型来研究这7种物质关于OAT1、OAT3、有机阴离子转运多肽1B1和1B3、有机阳离子转运体2、多药和毒素外排蛋白1以及P-糖蛋白的转运特性，并研究了两种最具潜力的候选物质的OAT1/OAT3转运动力学。所有这7种潜在生物标志物均被鉴定为OAT1和OAT3的底物（吲哚乳酸和吲哚乙酰谷氨酰胺对OAT1的K值分别为319.4±31.9μM和609.8±129.2μM；对OAT3的K值分别为290.1±41.0μM和161.4±20.3μM），而与OAT1/OAT3介导的摄取相比，其他转运体对这些物质的转运完全不存在或水平很低。总体而言，基于目前体外研究结果与之前体内研究结果的一致性，以及饮食对所研究的潜在生物标志物处置的可能影响，吲哚乳酸和吲哚乙酰谷氨酰胺成为最有希望进一步验证作为OAT1/OAT3介导的肾脏药物相互作用生物标志物的候选物质。
