Global Drug Metabolism and Pharmacokinetics, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3, Tokodai, Tsukuba, Ibaraki, 300-2635, Japan (Y.N., S.I.)
Global Drug Metabolism and Pharmacokinetics, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3, Tokodai, Tsukuba, Ibaraki, 300-2635, Japan (Y.N., S.I.).
Drug Metab Dispos. 2023 Sep;51(9):1077-1088. doi: 10.1124/dmd.122.000970. Epub 2023 Feb 28.
Transporter-mediated drug-drug interaction (DDI) is of clinical concern, and the quantitative prediction of DDIs is an indispensable part of drug development. Cell-based inhibition assays, in which a representative probe substrate and a potential inhibitor are coincubated, are routinely performed to assess the inhibitory potential of new molecular entities on drug transporters. However, the inhibitory effect of cyclosporine A (CsA) on organic anion transporting polypeptide (OATP) 1B1 is substantially potentiated with CsA preincubation, and this effect is both long-lasting and dependent on the preincubation time. This phenomenon has also been reported with transporters other than OATP1Bs, but it is considered more prevalent among OATP1Bs and organic cation transporters. Regulatory agencies have also noted this preincubation effect and have recommended that pharmaceutical companies consider inhibitor preincubation when performing in vitro OATP1B1 and OATP1B3 inhibition studies. Although the underlying mechanisms responsible for the preincubation effect are not fully understood, a -inhibition mechanism was recently demonstrated for OATP1B1 inhibition by CsA, in which CsA inhibited OATP1B1 not only extracellularly (-inhibition) but also intracellularly (-inhibition). Furthermore, the -inhibition potency of CsA was much greater than that of -inhibition, suggesting that -inhibition might be a key driver of clinical DDIs of CsA with OATP1B substrate drugs. Although confidence in transporter-mediated DDI prediction is generally considered to be low, the predictability might be further improved by incorporating the -inhibition mechanism into static and dynamic models for preincubation-dependent inhibitors of OATP1Bs and perhaps other transporters. SIGNIFICANCE STATEMENT: Preincubation time-dependent, long-lasting inhibition has been observed for OATP1B1 and other solute carrier transporters in vitro. Recently, a -inhibition mechanism for the preincubation effect of CsA on OATP1B1 inhibition was identified, with the -inhibition potency being greater than that of -inhibition. The concept of -inhibition may allow us to further understand the mechanism of transporter-mediated DDIs not only for OATP1B1 but also for other transporters and to improve the accuracy and confidence of DDI predictions.
药物-药物相互作用（DDI）的转运介导与临床密切相关，定量预测 DDI 是药物开发不可或缺的一部分。细胞抑制试验是常规进行的，其中代表性的探针底物和潜在抑制剂共同孵育，用于评估新分子实体对药物转运体的抑制潜力。然而，环孢素 A（CsA）预先孵育可显著增强其对有机阴离子转运多肽（OATP）1B1 的抑制作用，这种作用是持久的，并且依赖于预孵育时间。这种现象也已在除 OATP1Bs 以外的转运体中报道，但在 OATP1Bs 和有机阳离子转运体中更为常见。监管机构也注意到了这种预孵育效应，并建议制药公司在进行体外 OATP1B1 和 OATP1B3 抑制研究时考虑抑制剂的预孵育。虽然尚未完全了解导致预孵育效应的潜在机制，但最近证明 CsA 对 OATP1B1 的抑制作用存在 -抑制机制，其中 CsA 不仅在细胞外（-抑制），而且在细胞内（-抑制）抑制 OATP1B1。此外，CsA 的 -抑制效力远大于 -抑制效力，表明 -抑制可能是 CsA 与 OATP1B 底物药物发生临床 DDI 的关键驱动因素。尽管一般认为转运介导的 DDI 预测的置信度较低，但通过将 -抑制机制纳入 OATP1Bs 和其他转运体的静态和动态模型中，预测性可能会进一步提高。
在体外观察到 OATP1B1 和其他溶质载体转运体的预孵育时间依赖性、持久的抑制作用。最近，确定了 CsA 对 OATP1B1 抑制的预孵育效应的 -抑制机制，-抑制效力大于 -抑制效力。-抑制的概念不仅可以使我们进一步了解 OATP1B1 等转运体介导的 DDI 的机制，还可以提高 DDI 预测的准确性和置信度。
