Rifampin Enhances the Glucose-Lowering Effect of Metformin and Increases OCT1 mRNA Levels in Healthy Participants

We evaluated the effect of the pregnane X receptor (PXR) agonist rifampin on metformin pharmacokinetics, organic cation transporter 1 (OCT1) and OCT2 mRNA levels, and glucose levels, using the oral glucose tolerance test (OGTT) in 16 healthy subjects. The glucose‐lowering effects of metformin were evaluated by OGTT before and after metformin treatment on days 1 and 2 and again on days 13 and 14 after a 10‐day course of rifampin. Rifampin increased the difference in maximum glucose levels (ΔGmax) by 41.9% (P = 0.024) and the area under the concentration–time curve (AUC) during the first 60 min after glucose ingestion (ΔAUCgluc60) by 54.5% (P = 0.020). Renal clearance (CLR) of metformin was increased by 16% (P = 0.008), but the systemic exposure was only slightly increased (13%, P = 0.049), possibly because of increased absorption. Rifampin increased OCT1 mRNA levels 4.1‐fold in peripheral blood cells (P = 0.001); however, OCT2 mRNA was not detected. Our results suggest that rifampin increases OCT1 expression and hepatic uptake of metformin, leading to enhanced glucose‐lowering action. Clinical Pharmacology & Therapeutics (2011) 89 3, 416–421. doi:10.1038/clpt.2010.266