Interaction of rosiglitazone and pioglitazone with organic cation transporters

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 H-3-MPP+ uptake with half maximal inhibitory concentration (IC50) of 7.4 +/- 1.2 mu M and 2.5 +/- 0.4 mu M, respectively. The mode of inhibition by rosiglitazone was further determined using kinetic analysis. We showed that rosiglitazone decreased the maximal transport (V-max) without affecting the transporter affinity (K-m), 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.