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基于生理的药代动力学模型与动态 PET 数据研究转运体抑制对小鼠肝胆清除的影响。

Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the Effects of Transporter Inhibition on Hepatobiliary Clearance in Mice.

机构信息

Radiopharmaceutical Science and Biopharmacy, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.

Department of Nuclear Medicine, University Hospital Zurich, Switzerland.

出版信息

Contrast Media Mol Imaging. 2018 Jun 3;2018:5849047. doi: 10.1155/2018/5849047. eCollection 2018.

DOI:10.1155/2018/5849047
PMID:29967572
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6008768/
Abstract

Physiologically based pharmacokinetic modelling (PBPK) is a powerful tool to predict pharmacokinetics based on physiological parameters and data from studies and assays. PBPK modelling in laboratory animals by noninvasive imaging could help to improve the translation towards human pharmacokinetics modelling. We evaluated the feasibility of PBPK modelling with PET data from mice. We used data from two of our PET tracers under development, [C]AM7 and [C]MT107. PET images suggested hepatobiliary excretion which was reduced after cyclosporine administration. We fitted the time-activity curves of blood, liver, gallbladder/intestine, kidney, and peripheral tissue to a compartment model and compared the resulting pharmacokinetic parameters under control conditions ([C]AM7 = 2; [C]MT107, = 4) and after administration of cyclosporine ([C]MT107, = 4). The modelling revealed a significant reduction in [C]MT107 hepatobiliary clearance from 35.2 ± 10.9 to 17.1 ± 5.6 l/min after cyclosporine administration. The excretion profile of [C]MT107 was shifted from predominantly hepatobiliary (CL/CL = 3.8 ± 3.0) to equal hepatobiliary and renal clearance (CL/CL = 0.9 ± 0.2). Our results show the potential of PBPK modelling for characterizing the effects of transporter inhibition on whole-body and organ-specific pharmacokinetics.

摘要

基于生理的药代动力学模型（PBPK）是一种强大的工具，可以根据生理参数和来自研究和测定的数据来预测药物动力学。通过非侵入性成像在实验室动物中进行 PBPK 模型构建，有助于改善向人体药代动力学模型的转化。我们评估了使用来自小鼠的 PET 数据进行 PBPK 建模的可行性。我们使用了正在开发的两种我们的 PET 示踪剂 [C]AM7 和 [C]MT107 的数据。PET 图像提示肝胆排泄，在环孢素给药后减少。我们将血液、肝脏、胆囊/肠道、肾脏和外周组织的时间-活性曲线拟合到一个房室模型中，并比较了在对照条件下（[C]AM7 = 2；[C]MT107 = 4）和环孢素给药后（[C]MT107 = 4）得到的药代动力学参数。模型揭示了 [C]MT107 的肝胆清除率从环孢素给药前的 35.2 ± 10.9 到 17.1 ± 5.6 l/min 显著降低。[C]MT107 的排泄模式从主要的肝胆（CL/CL = 3.8 ± 3.0）转变为相等的肝胆和肾清除（CL/CL = 0.9 ± 0.2）。我们的结果表明，PBPK 模型构建具有表征转运体抑制对全身和器官特异性药代动力学的影响的潜力。

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