Medicine Design, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut 06340.
Medicine Design, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut 06340.
J Pharm Sci. 2019 Jul;108(7):2476-2483. doi: 10.1016/j.xphs.2019.02.005. Epub 2019 Feb 20.
It is of great challenge to predict human brain penetration for substrates of multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), 2 major efflux transporters at blood-brain barrier. Thus, a physiologically based pharmacokinetic (PBPK) model with the incorporation of in vitro MDR1 and BCRP transporter function data and transporter protein expression levels has been developed. As such, it is crucial to generate MDR1 and BCRP substrate data with a high fidelity. In this study, 2 widely used human MDR1 cell lines from Borst and National Institutes of Health laboratories were evaluated using rodent brain penetration data, and the study suggested that the MDR1 expressed in Madin-Darby canine kidney (MDCK) cell line from National Institutes of Health laboratory predicted brain penetration better, particularly for compounds with a high passive permeability. In addition, human BCRP-MDCK cell line with 1 μM PSC833, a specific MDR1 inhibitor, demonstrated the ability to identify BCRP substrates without the confounding of endogenous canine Mdr1. Comparison of human BCRP and mouse Bcrp transporter functions revealed that the functional differences of BCRP between the 2 species is minimal. The incorporation of both the validated MDR1 and BCRP assays into our brain PBPK model has significantly improved the prediction for the brain penetration of MDR1 and BCRP substrates across species.
预测多药耐药蛋白 1（MDR1）和乳腺癌耐药蛋白（BCRP）这两种主要的血脑屏障外排转运体的人脑中的穿透率极具挑战性。因此，已经开发了一种包含体外 MDR1 和 BCRP 转运体功能数据和转运体蛋白表达水平的基于生理学的药代动力学（PBPK）模型。因此，生成具有高保真度的 MDR1 和 BCRP 底物数据至关重要。在这项研究中，使用啮齿动物脑穿透数据评估了来自 Borst 和美国国立卫生研究院实验室的 2 种广泛使用的人 MDR1 细胞系，研究表明，美国国立卫生研究院实验室的 Madin-Darby 犬肾（MDCK）细胞系中表达的 MDR1 更好地预测了脑穿透，尤其是对于具有高被动渗透性的化合物。此外，用 1 μMPSC833（一种特定的 MDR1 抑制剂）处理的人 BCRP-MDCK 细胞系具有识别 BCRP 底物的能力，而不会受到内源性犬 Mdr1 的干扰。人 BCRP 和小鼠 Bcrp 转运体功能的比较表明，这 2 个物种之间 BCRP 的功能差异很小。将经过验证的 MDR1 和 BCRP 测定法纳入我们的大脑 PBPK 模型中，大大提高了对跨物种 MDR1 和 BCRP 底物脑穿透的预测能力。
