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

Abstract

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 (.Gmax) by 41.9% (P = 0.024) and the area under the concentration- time curve (AUC) during the first 60 min after glucose ingestion (.AUCgluc60) 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.