PT - JOURNAL ARTICLE AU - Eugene C Chen AU - Xiaomin Liang AU - Sook Wah Yee AU - Sophie L Stocker AU - Ethan G Geier AU - Ligong Chen AU - Kathleen M Giacomini TI - Targeted Disruption of Organic Cation Transporter 3 (Oct3) Attenuates the Pharmacologic Response to Metformin AID - 10.1124/mol.114.096776 DP - 2015 Apr 28 TA - Molecular Pharmacology PG - mol.114.096776 4099 - http://molpharm.aspetjournals.org/content/early/2015/04/28/mol.114.096776.short 4100 - http://molpharm.aspetjournals.org/content/early/2015/04/28/mol.114.096776.full AB - Metformin, the most widely prescribed anti-diabetic 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 to wildtype mice (p < 0.001), indicating an important role of OCT3 in tissue distribution and elimination of the drug. Following oral doses, a significantly lower bioavailability was observed in knockout compared to wildtype mice (0.27 versus 0.58, p < 0.001). Importantly, metformin's effects on oral glucose tolerance were reduced in knockout compared with wildtype mice (30% versus 12% reduction, p < 0.05) along with its accumulation in skeletal muscle and adipose tissue (p < 0.05). Further, the effect of metformin on phosphorylation of AMP activated protein kinase, AMPK, and expression of glucose transporter type 4 was absent in the adipose tissue of Oct3-/- mice. Additional analysis revealed that an OCT3 3'UTR 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.