Fenofibrate down-regulates renal OCT2-mediated organic cation transport via PPARα-independent pathways.

Fibrate drugs, the peroxisome proliferator-activated receptor alpha (PPARα) agonists, are widely prescribed for the treatment of hyperlipidemia. The present study examined the effect of fibrate drugs on renal OCT2 activity in a heterologous cell system [Chinese hamster ovary (CHO-K1) cells stably transfected with rabbit (rb) OCT2], LLC-PK1, and intact mouse renal cortical slices. We found that both in the CHO-K1 cells expressing rbOCT2 and in LLC-PK1 cells, fenofibrate significantly inhibited [³H]-MPP⁺ uptake whereas clofibrate and WY14643 had no effect. Surprisingly, the inhibitory effect of fenofibrate was not attenuated by GW6471, a PPARα antagonist, indicating that the inhibitory process observed was via a PPARα-independent pathway. Fenofibrate decreased [³H]-MPP⁺ uptakes through a reduction of the maximal transport (J(max)) but without effect on the transporter affinity (K(t)) corresponding to a decrease in membrane expression of OCT2. Since the inhibitory effect of fenofibrate was not prevented by pretreatment with cycloheximide, its inhibitory action did not involve an inhibition of protein synthesis. Similar to the effect seen in the cell-cultured system, the inhibitory effect of fenofibrate was also observed in intact renal cortical slices. Taken together, our data showed that fenofibrate decreased the activity of OCT2 by reducing the number of functional transporters on the membrane, which is likely to be a PPARα-independent pathway.