Quantitative Contributions of Hepatic and Renal Organic Cation Transporters to the Clinical Pharmacokinetic Cimetidine–Metformin Interaction

The widely prescribed oral anti‐diabetic drug metformin is eliminated unchanged in the urine primarily through active tubular secretion. This process is mediated by organic cation transporter 2 (OCT2), an uptake transporter expressed on the basolateral membrane of renal proximal tubule cells. Metformin uptake into the liver, the site of action, is mediated by organic cation transporter 1 (OCT1), which is expressed on the sinusoidal membrane of hepatocytes. Sixteen healthy adults participated in a clinical pharmacokinetic drug–drug interaction study in which they were orally administered metformin (50 mg) as a dual OCT1/2 substrate alone (baseline) and with cimetidine (400 mg) as an OCT inhibitor. Relative to baseline, metformin systemic plasma exposure increased by 24% ( p < 0.05) in the presence of cimetidine, which was accompanied by a disproportional decrease (8%) in metformin renal clearance ( p = 0.005). Genetic variants of OCT1 and OCT2 moderately impacted the significance and magnitude of the interaction. Collectively, we hypothesized that the cimetidine–metformin interaction involves inhibition of hepatic OCT1 as well as renal OCT2. We tested this hypothesis by developing a physiologically based pharmacokinetic (PBPK) model and assessing potential OCT biomarkers in plasma and urine to gain mechanistic insight into the transporters involved in this interaction. The PBPK model predicted that cimetidine primarily inhibits hepatic OCT1 and, to a lesser extent, renal OCT2. The unchanged renal clearance of potential OCT2 biomarkers following cimetidine exposure supports a minimal role for renal OCT2 in this interaction.