Organic cation transporter (OCT)1 and OCT2 mediate hepatic uptake and secretory renal clearance of metformin, respectively. Pharmacokinetic/pharmacodynamic (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 unbound glomerular filtration rate, and volume of distribution was reduced 3.5-fold in Oct1/Oct2-knockout mice. Oral bioavailability was not affected (F = 64 ± 4 versus 59 ± 11; knockout versus wild type). Liver- and kidney-to-plasma concentration ratios were decreased in Oct1/Oct2-knockout mice 4.2- and 2.5-fold, respectively. The 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 area under the curve (AUC) lowering by metformin was not impaired in Oct1/Oct2-knockout mice at the five dose levels tested (ED50 = 151 versus 110 mg/kg; glucose lowering at highest dose = 42 ± 1 versus 39 ± 4%; knockout versus wild type); however, higher systemic metformin exposures were necessary in knockout mice to elicit the same effect (half-maximal efficacious AUC = 70 versus 26 μg x h/ml). Despite major changes in metformin clearance and volume of distribution in Oct1/Oct2-knockout mice, tissue drug exposure and PD were not affected. These findings challenge the presumption that systemic OCT inhibition will affect metformin pharmacology.