Pharmacokinetics and Safety Department, Drug Research Center, Kaken Pharmaceutical Co., Ltd., Kyoto, Japan (T.T.) and Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (T.T., Y.M., A.F., Y.K.).
Pharmacokinetics and Safety Department, Drug Research Center, Kaken Pharmaceutical Co., Ltd., Kyoto, Japan (T.T.) and Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (T.T., Y.M., A.F., Y.K.)
Drug Metab Dispos. 2020 Sep;48(9):750-758. doi: 10.1124/dmd.120.000020. Epub 2020 Jul 2.
Quantitative assessment of drug-drug interactions (DDIs) via organic anion transporting polypeptide (OATP) 1B1 is one of the key issues in drug development. Although OATP1B1 inhibition exhibits unique characteristics, including preincubation dependence for some inhibitors, a limited approach has been attempted based on the static model that considers such preincubation dependence in the prediction of DDIs via OATP1B1. The present study aimed to establish the prediction of DDIs via OATP1B1 using preincubation-dependent inhibitors based on the static model and incorporating both inactivation and recovery of OATP1B1 activity. Cyclosporine A was selected as a preincubation-dependent inhibitor, as well as five substrates that include probes and pharmaceuticals. The inhibition ratio (R value) calculated on the basis of a conventional static model, considering inhibition of OATP1B1 and contribution ratio of OATP1B1 to the overall hepatic uptake, was much lower than the reported AUC ratio, even when IC values were estimated after preincubation conditions. Conversely, the R value that was estimated by considering inactivation and recovery parameters was closer to the AUC ratio. The R value that was calculated assuming the complete contribution of OATP1B1 was much higher than the AUC ratio, avoiding false-negative prediction. The R value estimated by considering inactivation and recovery for another combination of a preincubation-dependent inhibitor, asunaprevir, and substrate drug, rosuvastatin, was also closer to the AUC ratio. Thus, R values calculated based on such OATP1B1 kinetics would be potential alternative indexes for the quantitative prediction of OATP1B1-mediated DDIs using preincubation-dependent inhibitors, although this prediction is affected by estimation of the contribution ratio of substrates. SIGNIFICANCE STATEMENT: Static model-based quantitative prediction of organic anion transporting polypeptide 1B1-mediated drug-drug interactions induced by preincubation-dependent inhibitors was newly proposed to avoid false-negative prediction.
定量评估药物-药物相互作用（DDIs）通过有机阴离子转运多肽（OATP）1B1 是药物开发的关键问题之一。尽管 OATP1B1 抑制具有独特的特性，包括一些抑制剂的预孵育依赖性，但基于静态模型的有限方法已经尝试过，该模型考虑了预孵育依赖性在通过 OATP1B1 预测 DDI 中的作用。本研究旨在建立基于静态模型并结合 OATP1B1 活性失活和恢复的方法，预测通过 OATP1B1 的 DDI，使用预孵育依赖性抑制剂。环孢素 A 被选为预孵育依赖性抑制剂，以及包括探针和药物在内的五种底物。基于常规静态模型计算的抑制率（R 值），考虑到 OATP1B1 的抑制作用和 OATP1B1 对整体肝摄取的贡献比，远低于报告的 AUC 比，即使在预孵育条件下估计 IC 值也是如此。相反，考虑失活和恢复参数的 R 值更接近 AUC 比。假设 OATP1B1 的完全贡献的 R 值远高于 AUC 比，避免了假阴性预测。考虑到另一种预孵育依赖性抑制剂asunaprevir 和底物药物rosuvastatin 的组合的失活和恢复参数的 R 值，也更接近 AUC 比。因此，基于这种 OATP1B1 动力学计算的 R 值可能是使用预孵育依赖性抑制剂定量预测 OATP1B1 介导的 DDI 的潜在替代指标，尽管这种预测受到底物贡献比的估计的影响。
为了避免假阴性预测，我们新提出了基于静态模型的定量预测预孵育依赖性抑制剂诱导的 OATP1B1 介导的药物-药物相互作用的方法。
