Abstract

Previously, we have shown that the inhibition of the transporter-mediated hepatic uptake of cerivastatin (CER) by cyclosporin A (CsA) could, at least partly, explain a pharmacokinetic interaction between these drugs in humans. In the present study, we have examined the effect of CsA on the in vivo disposition of CER in rats and the in vitro uptake of [¹⁴C]CER in isolated rat hepatocytes in an attempt to evaluate the effect of inhibition of transporter-mediated hepatic uptake on the in vivo CER disposition. The steady-state plasma concentration of CER increased 1.4-fold when coadministered with CsA up to a steady-state blood concentration of 4 μM. Studies of [¹⁴C]CER uptake into isolated rat hepatocytes showed saturable transport, with the saturable portion accounting for more than 80% of the total uptake. CsA competitively inhibited the uptake of [¹⁴C]CER with a K_i of 0.3 μM. The IC₅₀ for the uptake of [¹⁴C]CER in the absence and presence of rat plasma was 0.2 and 2.3 μM, respectively. The in vivo hepatic uptake of [¹⁴C]CER evaluated by the liver uptake index method was also inhibited by CsA in a dose-dependent manner. On the other hand, CsA did not inhibit the metabolism of [¹⁴C]CER in rat microsomes. The in vitro and in vivo correlation analysis revealed that this pharmacokinetic interaction between these drugs in rats could be quantitatively explained by the inhibition of transporter-mediated hepatic uptake. Thus, this drug-drug interaction in rats is predominantly caused by the transporter-mediated uptake process.