Targeted disruption of organic cation transporter 3 attenuates the pharmacologic response to metformin

• Published in: Molecular pharmacology Vol. 88; no. 1; pp. 75 - 83
• Main Authors: Chen, Eugene C, Liang, Xiaomin, Yee, Sook Wah, Geier, Ethan G, Stocker, Sophie L, Chen, Ligong, Giacomini, Kathleen M
• Format: Journal Article
• Language: English
• Published: United States The American Society for Pharmacology and Experimental Therapeutics 01.07.2015
• Subjects: 3' Untranslated Regions; Adipose Tissue - metabolism; Animals; Biological Availability; Cell Line, Tumor; Gene Expression Regulation - drug effects; Glucose - metabolism; HCT116 Cells; Healthy Volunteers; Hep G2 Cells; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacokinetics; Injections, Intraperitoneal; Male; Metformin - administration & dosage; Metformin - pharmacokinetics; Mice; Mice, Knockout; Muscle, Skeletal - metabolism; Organic Cation Transport Proteins - genetics; Organic Cation Transport Proteins - metabolism; Polymorphism, Single Nucleotide; Tissue Distribution
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.114.096776

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 (OCT3, SLC22A3), 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 (P < 0.001), 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 (0.27 versus 0.58, P < 0.001). Importantly, metformin's effect on the plasma glucose concentration-time curve was reduced in knockout compared with wild-type mice (12 versus 30% reduction, respectively, P < 0.05) along with its accumulation in skeletal muscle and adipose tissue (P < 0.05). 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.