Abstract

The mechanism involved in the clinically relevant drug-drug interaction (DDI) between cerivastatin (CER) and cyclosporin A (CsA) has not yet been clarified. In the present study, we examined the possible roles of transporter-mediated hepatic uptake in this DDI. The uptake of [¹⁴C]CER into human hepatocytes prepared from three different donors was examined. Kinetic analyses revealedK_m values for the uptake of [¹⁴C]CER within the range of 3 to 18 μM, suggesting that more than 70% of the total uptake at therapeutic CER concentrations was accounted for by a saturable process, i.e., transporter-mediated uptake. This uptake was inhibited by CsA withK_i values of 0.3 to 0.7 μM. The uptake of [¹⁴C]CER was also examined in human organic anion transporting polypeptide-2 (OATP2)-expressing Madin-Darby canine kidney cells (MDCKII). Saturable OATP2-mediated uptake of [¹⁴C]CER was observed and was also inhibited by CsA, with a K_i value of 0.2 μM. These results suggest that the DDI between CER and CsA involves the inhibition of transporter-mediated uptake of CER and, at least in part, its OATP2-mediated uptake. The effect of CsA on the in vitro metabolism of [¹⁴C]CER was also examined. The metabolism of [¹⁴C]CER was inhibited by CsA with an IC₅₀value of more than 30 μM. From these results, we conclude that the DDI between CER and CsA is mainly due to the inhibition of transporter (at least partly OATP2)-mediated uptake in the liver.