Pharmacokinetics, Dynamics and Metabolism, Translational Medicine and Early Development, R&D Operations, Sanofi, Tokyo, Japan.
Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, Yokohama, Japan.
Pharmacol Ther. 2017 Sep;177:67-80. doi: 10.1016/j.pharmthera.2017.02.042. Epub 2017 Feb 27.
Preincubation with cyclosporin A (CsA), a potent inhibitor of organic anion transporting polypeptide 1B1 (OATP1B1) and OATP1B3, enhanced its inhibitory effects on these transporters in vitro. A similar effect was observed upon preincubation with some other inhibitors. Removing these from the incubation media did not readily reverse the inhibition on OATP1B1 and OATP1B3. This preincubation-dependent long-lasting inhibition appeared to be related to CsA concentration in the cells in addition to that in the incubation media. Thus, we hypothesized that CsA inhibits OATP1B1 and OATP1B3 from inside (trans-inhibition) as well as outside (cis-inhibition) the cells and constructed the cis- and trans-inhibition model. The enhanced inhibitory effect of CsA on OATP1B1 observed after preincubation was quantitatively described using K and K as inhibition constants for cis- and trans-inhibitions, respectively. In addition, a long-lasting inhibition was also described by this model. Additional factors taken into consideration when simulating in vivo pharmacokinetic alterations by CsA are potential inhibition by AM1, a major metabolite of CsA, which has been reported to inhibit OATP1B1 and OATP1B3. Based on the physiologically based pharmacokinetic model incorporating trans- and cis-inhibition of OATP1B1 by CsA, the simulation showed that OATP1B1-mediated drug-drug interaction with CsA was suggested to be time-dependent also in vivo although further clinical studies are required for confirmation.
环孢素 A（CsA）是有机阴离子转运多肽 1B1（OATP1B1）和 OATP1B3 的有效抑制剂，预孵育可增强其对这些转运体的体外抑制作用。预孵育其他一些抑制剂也观察到类似的效果。将这些抑制剂从孵育介质中去除并不会轻易逆转对 OATP1B1 和 OATP1B3 的抑制作用。这种预孵育依赖性的持久抑制作用似乎与细胞内（反式抑制）和细胞外（顺式抑制）CsA 浓度有关。因此，我们假设 CsA 从细胞内外（顺式和反式抑制）抑制 OATP1B1 和 OATP1B3，并构建了顺式和反式抑制模型。使用 cis 和 trans 抑制的抑制常数 K 和 K 定量描述了预孵育后观察到的 CsA 对 OATP1B1 的增强抑制作用。此外，该模型还描述了持久抑制作用。在模拟 CsA 对体内药代动力学改变时，还需要考虑到 AM1 的潜在抑制作用，AM1 是 CsA 的主要代谢物，据报道它可抑制 OATP1B1 和 OATP1B3。基于包含 CsA 对 OATP1B1 的顺式和反式抑制的基于生理学的药代动力学模型，模拟表明 OATP1B1 介导的与 CsA 的药物相互作用在体内也是时间依赖性的，尽管需要进一步的临床研究来证实。
