PT - JOURNAL ARTICLE AU - J. William Higgins AU - David W. Bedwell AU - Maciej J Zamek-Gliszczynski TI - Ablation of Both Oct1 and Oct2 Alters Metformin Pharmacokinetics But Has No Effect on Tissue Drug Exposure and Pharmacodynamics AID - 10.1124/dmd.112.044875 DP - 2012 Mar 09 TA - Drug Metabolism and Disposition PG - dmd.112.044875 4099 - http://dmd.aspetjournals.org/content/early/2012/03/09/dmd.112.044875.short 4100 - http://dmd.aspetjournals.org/content/early/2012/03/09/dmd.112.044875.full AB - OCT1 and OCT2 mediate hepatic uptake and secretory renal clearance of metformin, respectively. PK/PD implications of simultaneous impairment of both transporters, such as by systemic pan-OCT inhibition, have not been studied directly. At present metformin PK/PD, distribution, and excretion were studied in Oct1/Oct2-knockout mice. Metformin clearance was reduced 4.5 fold from renal blood flow to glomerular filtration rate (GFR), and volume of distribution was reduced 3.5 fold in Oct1/Oct2-knockout mice. Oral bioavailability was not affected (F = 64 ± 4 vs. 59 ± 11; knockout vs. wild type). Liver- and kidney-to-plasma concentration ratios were decreased in Oct1/Oct2-knockout mice 4.2 and 2.5 fold, respectively. Surprisingly, 2.9-fold increase in oral metformin exposure and reduced tissue partitioning yielded little-to-no net change in tissue drug concentrations. Absolute kidney exposure was unchanged (knockout:wild type = 1.1 ± 0.2), and liver exposure was only modestly decreased (knockout:wild type = 0.6 ± 0.1). Oral glucose AUC lowering by metformin was not impaired in Oct1/Oct2-knockout mice at the five dose levels tested [ED50 = 151 vs. 110 mg/kg; glucose lowering at highest dose = 42 ± 1 vs. 39 ± 4%; knockout vs. wild type); however, higher systemic metformin exposures were necessary in knockout mice to elicit the same effect (EAUC50 = 70 vs. 26 μg*hr/mL). Despite major changes in metformin clearance and volume of distribution in Oct1/Oct2-knockout mice, tissue drug exposure and pharmacodynamics were not affected. These findings challenge the presumption that systemic OCT inhibition will affect metformin pharmacology.