Evaluation of Potential Drug-drug Interactions of YH18421 in Triple Combination with metformin and DPP4 inhibitors

Metformin is the first-line treatment of type 2 diabetes, and DPP4 inhibitors are commonly used in combination therapy. YH18421, a novel G-protein coupled receptor agonist, has shown promise as a potential treatment for type 2 diabetes. This study evaluated the drug-drug interaction potential of YH18421 when co-administered with metformin and DPP4 inhibitors. YH18421 exhibited minimal potential for cytochrome P450-mediated drug-drug interactions but was an inhibitor of several transporters, including efflux transporters (MDR1 and BCRP) and uptake transporters (OATP1B1, OATP1B3, OAT1, OAT3, and OCT2). YH18421, metformin, and DPP4 inhibitors (linagliptin or sitagliptin) were orally administered to mice, either alone or in combination. The pharmacokinetic effects of YH18421 on linagliptin and sitagliptin were generally negligible, suggesting that co-administration of YH18421 is unlikely to pose significant pharmacological and safety concerns. However, YH18421 showed the potential to alter metformin pharmacokinetics. Metformin is a substrate of OCT2, facilitating its uptake into renal tubular cells for subsequent urinary excretion. Coadministration of YH18421 increased the systemic exposure of metformin, which resulted from the reduction of renal excretion of metformin, likely due to YH18421-mediated OCT2 inhibition. Although metformin has a wide therapeutic index, clinical evaluation could be warranted to assess the extent of OCT2 inhibition-mediated alterations by YH18421.