Cyclosporine Inhibition of Hepatic and Intestinal CYP3A4, Uptake and Efflux Transporters: Application of PBPK Modeling in the Assessment of Drug-Drug Interaction Potential
Cyclosporine Inhibition of Hepatic and Intestinal CYP3A4, Uptake and Efflux Transporters: Application of PBPK Modeling in the Assessment of Drug-Drug Interaction Potential
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DOI：
10.1007/s11095-012-0918-y
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发表时间：
2013-03-01
影响因子：
3.7
通讯作者：
Galetin, Aleksandra
中科院分区：
文献类型：
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作者：
Gertz, Michael;Cartwright, Catherine M.;Galetin, Aleksandra
应用基于生理学的药代动力学（PBPK）模型研究环孢素及其代谢产物AM 1降低肝和肠摄取和外排转运蛋白活性的后果。在HEK 293细胞+/-预孵育中研究环孢素和AM 1对OATP 1B 1、OATP 1B 3和OATP 2B 1的抑制效力。在Matlab中实现的环孢素PBPK模型用于评估与肝脏和肠道不同过程（摄取、流出和代谢）的相互作用潜力（+/-代谢产物），并定量预测与瑞格列奈的药物-药物相互作用。环孢素和AM 1是OATP 1B 1和OATP 1B 3的强效抑制剂，预孵育后的IC 50范围为0.019-0.093 μ M。环孢菌素PBPK模型预测对肝脏摄取转运蛋白的相互作用潜力最高，OATP 1B 1活性最大降低> 70%;对肝脏外排和代谢的影响极小。相比之下，由于环孢素肠细胞浓度相对于未结合的肝入口高50倍，80-97%的肠P-gp和CYP 3A 4活性降低。纳入AM 1导致OATP 1B 1/1B 3活性的预测最大降低略有增加。良好的可预测性环孢素瑞格列奈DDI和剂量交错的影响是illustrated.本研究突出了PBPK建模的应用，定量预测转运蛋白介导的DDI与P450抑制的同时考虑。
To apply physiologically-based pharmacokinetic (PBPK) modeling to investigate the consequences of reduction in activity of hepatic and intestinal uptake and efflux transporters by cyclosporine and its metabolite AM1.Inhibitory potencies of cyclosporine and AM1 against OATP1B1, OATP1B3 and OATP2B1 were investigated in HEK293 cells +/- pre-incubation. Cyclosporine PBPK model implemented in Matlab was used to assess interaction potential (+/- metabolite) against different processes (uptake, efflux and metabolism) in liver and intestine and to predict quantitatively drug-drug interaction with repaglinide.Cyclosporine and AM1 were potent inhibitors of OATP1B1 and OATP1B3, IC50 ranging from 0.019-0.093 mu M following pre-incubation. Cyclosporine PBPK model predicted the highest interaction potential against liver uptake transporters, with a maximal reduction of > 70% in OATP1B1 activity; the effect on hepatic efflux and metabolism was minimal. In contrast, 80-97% of intestinal P-gp and CYP3A4 activity was reduced due to the 50-fold higher cyclosporine enterocytic concentrations relative to unbound hepatic inlet. The inclusion of AM1 resulted in a minor increase in the predicted maximal reduction of OATP1B1/1B3 activity. Good predictability of cyclosporine-repaglinide DDI and the impact of dose staggering are illustrated.This study highlights the application of PBPK modeling for quantitative prediction of transporter-mediated DDIs with concomitant consideration of P450 inhibition.