Xiaofeng Liang

Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.Metformin, the most widely prescribed antidiabetic drug, requires transporters to enter tissues involved in its pharmacologic action, including liver, kidney, and peripheral tissues. Organic cation transporter 3, expressed ubiquitously, transports metformin, but its in vivo role in metformin response is not known. Using Oct3 knockout mice, the role of the transporter in metformin pharmacokinetics and pharmacodynamics was determined. After an intravenous dose of metformin, a 2-fold decrease in the apparent volume of distribution and clearance was observed in knockout compared with wild-type mice, indicating an important role of OCT3 in tissue distribution and elimination of the drug. After oral doses, a significantly lower bioavailability was observed in knockout compared with wild-type mice. Importantly, metformin's effect on the plasma glucose concentration-time curve was reduced in knockout compared with wild-type mice along with its accumulation in skeletal muscle and adipose tissue. Furthermore, the effect of metformin on phosphorylation of AMP activated protein kinase, and expression of glucose transporter type 4 was absent in the adipose tissue of Oct3-/- mice. Additional analysis revealed that an OCT3 3′ untranslated region variant was associated with reduced activity in luciferase assays and reduced response to metformin in 57 healthy volunteers. These findings suggest that OCT3 plays an important role in the absorption and elimination of metformin and that the transporter is a critical determinant of metformin bioavailability, clearance, and pharmacologic action.

© 2015 American Chemical Society.The biguanide metformin is widely used as first-line therapy for the treatment of type 2 diabetes. Predominately a cation at physiological pH's, metformin is transported by membrane transporters, which play major roles in its absorption and disposition. Recently, our laboratory demonstrated that organic cation transporter 1, OCT1, the major hepatic uptake transporter for metformin, was also the primary hepatic uptake transporter for thiamine, vitamin B1. In this study, we tested the reverse, i.e., that metformin is a substrate of thiamine transporters. Our study demonstrated that human THTR-2, SLC19A3, which is highly expressed in the small intestine, but not hTHTR-1, transports metformin and other cationic compounds. The uptake mechanism for hTHTR-2 was pH and electrochemical gradient sensitive. Furthermore, metformin as well as other drugs including phenformin, chloroquine, verapamil, famotidine, and amprolium inhibited hTHTR-2 mediated uptake of both thiamine and metformin. Species differences in the substrate specificity of THTR-2 between human and mouse orthologues were observed. Taken together, our data suggest that hTHTR-2 may play a role in the intestinal absorption and tissue distribution of metformin and other organic cations and that the transporter may be a target for drug-drug and drug-nutrient interactions.