Effects of Trimethoprim on Three Previously Proposed Putative Biomarkers for OCT2 / MATE ‐Mediated Renal Drug‐Drug Interactions in Healthy Volunteers

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 IC 50 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 IC 50 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.