Interaction of rosiglitazone and pioglitazone with organic cation transporters

Abstract

Thiazolidinedione drugs (TZDs) are used in the treatment of type 2 diabetes mellitus (DM). This study aimed to investigate the potential influence of TZDs on organic cation transporters (OCTs). Such interactions were examined using Chinese hamster ovary (CHO-K1) cells stably and singly transfected with rabbit (rb)OCT1 and rbOCT2, and in cells that endogenously express OCT1 (HepG2 cells) and OCT2 (LLC-PK1 cells). Rosiglitazone but not pioglitazone inhibited OCT1-and OCT2-mediated 3H-MPP+ uptake with half maximal inhibitory concentration (IC50) of 7.4±1.2 μM and 2.5±0.4 μM, respectively. The mode of inhibition by rosiglitazone was further determined using kinetic analysis. We showed that rosiglitazone decreased the maximal transport (Vmax) without affecting the transporter affinity (Km), indicating that the inhibitory effect of rosiglitazone on OCT1 and OCT2 entails a noncompetitive mechanism. Similarly, the inhibitory effect of rosiglitazone on MPP+ uptake was observed in OCT1 and OCT2 endogenously expressed. We conclude that rosiglitazone may inhibit transport activity of OCT1 and OCT2 by interfering with a non-substrate-binding site on the transporters. Since rosiglitazone is used in combination with other drugs to treat DM-related diseases, its inhibitory effect on OCTs may influence the pharmacokinetic of cationic drugs.