RT Journal Article
SR Electronic
T1 Ablation of Both Oct1 and Oct2 Alters Metformin Pharmacokinetics But Has No Effect on Tissue Drug Exposure and Pharmacodynamics
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.112.044875
DO 10.1124/dmd.112.044875
A1 Higgins, J. William
A1 Bedwell, David W.
A1 Zamek-Gliszczynski, Maciej J
YR 2012
UL http://dmd.aspetjournals.org/content/early/2012/03/09/dmd.112.044875.abstract
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.