Pharmacokinetic Interaction between Metformin and Verapamil in Rats: Inhibition of the OCT2-Mediated Renal Excretion of Metformin by Verapamil

Abstract

The incidence of hypertension in diabetic patients has been increasing and contributing to the high mortality of diabetic patients. Recently, verapamil use was found to lower fasting blood glucose levels in diabetic patients, which led to a new indication of verapamil as combination treatment with anti-diabetic agents such as metformin. As pharmacokinetic (PK) interaction can affect drug efficacy and safety in drug combination, their PK-based interaction is recommended to be evaluated in preclinical levels as well as clinical levels. In case of metformin and verapamil, organic cation transporter (OCT) 1 and 2 primarily mediate metformin distribution to the liver and its elimination into urine, whereas cytochrome P450 is responsible for the hepatic metabolism of verapamil. Verapamil is also known as a potential OCT2 inhibitor. Thus, PK interaction between metformin (30 mg/kg) and verapamil (20 mg/kg) were investigated after their simultaneous administration to rats. In our results, verapamil inhibited the OCT2-mediated renal excretion of metformin, subsequently leading to increase of the systemic exposure of metformin. In contrast, metformin did not influence the pharmacokinetic pattern of verapamil. Although the further clinical investigation is required, our finding suggests a possibility of OCT2-mediated interaction of metformin and verapamil.