RT Journal Article
SR Electronic
T1 IN VITRO AND IN VIVO CORRELATION OF THE INHIBITORY EFFECT OF CYCLOSPORIN A ON THE TRANSPORTER-MEDIATED HEPATIC UPTAKE OF CERIVASTATIN IN RATS
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1468
OP 1475
DO 10.1124/dmd.32.12.1468
VO 32
IS 12
A1 Yoshihisa Shitara
A1 Masaru Hirano
A1 Yasuhisa Adachi
A1 Tomoo Itoh
A1 Hitoshi Sato
A1 Yuichi Sugiyama
YR 2004
UL http://dmd.aspetjournals.org/content/32/12/1468.abstract
AB 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 Ki 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. The American Society for Pharmacology and Experimental Therapeutics