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Effects of Trimethoprim on Three Previously Proposed Putative Biomarkers for OCT2/MATE-Mediated Renal Drug-Drug
Jana Picurová1, Fabian Müller1,2, Daniel Auge1
1Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Abstract:
Regulatory agencies request the assessment of the potential of new drugs to cause transporter-mediated drug-drug interactions (DDI). This assessment can be improved by integrating endogenous biomarkers during drug development. Regarding the renal excretion of drugs such as metformin, the organic cation transporter (OCT) 2 and multidrug and toxin extrusion proteins (MATE) 1 and 2-K are of major importance. However, fully validated, sensitive, and specific biomarkers for these transporters are still lacking. In previous in vivo and in vitro studies, 5-aminovaleric acid betaine (5AVAB), serotonin (5HT), and 1-methylhistamine (1MH) emerged as promising biomarker candidates for OCT2/MATE-mediated DDI. Therefore, we further investigated their suitability for clinical risk assessment by evaluating the effects of the OCT2/MATE inhibitor trimethoprim in healthy volunteers and by determining IC50 values for the inhibition of OCT2- and/or MATE1-mediated uptake of the potential biomarkers by trimethoprim, cimetidine, pyrimethamine, and dolutegravir in vitro. Trimethoprim reduced the amount excreted into urine of 5AVAB, 5HT, and 1MH in vivo by 95.1 ± 5.67%, 78.9 ± 6.56%, and 51.9 ± 14.3%, respectively (all P < 0.001) as well as the renal clearance of 5AVAB and 5HT by 93.6 ± 5.85% and 73.8 ± 12.8%, respectively (both P < 0.001). When comparing the IC50 values with unbound inhibitor plasma concentrations, trimethoprim, cimetidine, and pyrimethamine preferentially inhibit the MATE1-mediated transport, whereas dolutegravir inhibits the OCT2-mediated transport of the biomarker candidates. In conclusion, this study further supports the suitability of 5-aminovaleric acid betaine (5AVAB), serotonin (5HT), and 1-methylhistamine (1MH) as promising biomarkers for OCT2/MATE-mediated DDI.
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