In vitro and in vivo correlation of the inhibitory effect of cyclosporin A on the transporter-mediated hepatic uptake of cerivastatin in rats.
In vitro and in vivo correlation of the inhibitory effect of cyclosporin A on the transporter-mediated hepatic uptake of cerivastatin in rats.
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DOI：
10.1124/dmd.32.12.1468
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发表时间：
2004-12
期刊：
影响因子：
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通讯作者：
Y. Shitara;M. Hirano;Y. Adachi;T. Itoh;Hitoshi Sato;Y. Sugiyama
中科院分区：
文献类型：
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作者：
Y. Shitara;M. Hirano;Y. Adachi;T. Itoh;Hitoshi Sato;Y. Sugiyama
以前，我们已经表明，环孢菌素A（CsA）对西立伐他汀（CER）转运蛋白介导的肝摄取的抑制至少可以部分解释这些药物在人体内的药代动力学相互作用。在本研究中，我们研究了CsA对CER在大鼠体内处置的影响，以及[14 C]CER在离体大鼠肝细胞中的体外摄取，以评估抑制转运蛋白介导的肝摄取对CER在体内处置的影响。当与CsA联合给药时，CER的稳态血药浓度增加1.4倍，达到4 μ M的稳态血药浓度。[14 C]CER摄取到离体大鼠肝细胞中的研究显示可饱和转运，可饱和部分占总摄取的80%以上。CsA竞争性抑制[14C]CER的摄取，Ki为0.3 μ M。在不存在和存在大鼠血浆的情况下，[14 C]CER摄取的IC 50分别为0.2和2.3 μ M。用肝摄取指数法评价的[14C]CER的体内肝摄取也被CsA以剂量依赖性方式抑制。另一方面，CsA不抑制[14 C]CER在大鼠微粒体中的代谢。体外和体内相关性分析表明，这些药物在大鼠体内的药代动力学相互作用可以通过抑制转运蛋白介导的肝脏摄取来定量解释。因此，大鼠中的药物相互作用主要由转运蛋白介导的摄取过程引起。
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 microM. 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 microM. The IC50 for the uptake of [14C]CER in the absence and presence of rat plasma was 0.2 and 2.3 microM, 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.