Prediction of Cyclosporin-Mediated Drug Interaction Using Physiologically Based Pharmacokinetic Model Characterizing Interplay of Drug Transporters and Enzymes.
Prediction of Cyclosporin-Mediated Drug Interaction Using Physiologically Based Pharmacokinetic Model Characterizing Interplay of Drug Transporters and Enzymes.
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使用表征药物转运体和酶相互作用的基于生理学的药代动力学模型预测环孢菌素介导的药物相互作用
DOI：
10.3390/ijms21197023
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发表时间：
2020-09-24
影响因子：
5.6
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Yang Y;Li P;Zhang Z;Wang Z;Liu L;Liu X
摄取转运蛋白有机阴离子转运多肽（OATP）、外排转运蛋白（P-gp、BCRP和MRP2）和细胞色素P450酶（CYP450s）在肝脏、肠或肾脏中广泛表达。它们协调一致地控制药物处置，称为“转运蛋白和酶的相互作用”。 Cyclosporine A (CsA) 是 OATP、P-gp、MRP2、BCRP 和 CYP3As 的抑制剂。 CsA 与受害药物的药物相互作用 (DDI) 通过转运蛋白和酶的紊乱相互作用发生。我们的目的是建立一个基于全身生理学的药代动力学（PBPK）模型，预测CsA和九种受害药物（包括阿托伐他汀、西立伐他汀、普伐他汀、瑞舒伐他汀、氟伐他汀、辛伐他汀、洛伐他汀、瑞格列奈和波生坦）的处置，以及CsA与九种受害药物的药物相互作用（DDI），以研究酶和转运蛋白在肝脏中的综合作用。肠道和肾脏对药物分布的影响。将预测与观察结果进行比较。大多数预测与观测值的误差在 0.5-2.0 倍之内。阿托伐他汀代表调查了转运蛋白和 CYP3A 对阿托伐他汀处置的个体贡献及其综合效应。对阿托伐他汀处置的贡献是肝脏 OATP >> 肝脏 CYP3A > 肠道 CYP3As ≈ 外排转运蛋白 (P-gp/BCRP/MRP2)。结果表明，所开发的表征酶和转运蛋白相互作用的 PBPK 模型成功应用于预测 10 种 OATP 底物和 CsA 与 9 种受害药物的 DDI 的药代动力学。
Uptake transporter organic anion transporting polypeptides (OATPs), efflux transporters (P-gp, BCRP and MRP2) and cytochrome P450 enzymes (CYP450s) are widely expressed in the liver, intestine or kidney. They coordinately work to control drug disposition, termed as “interplay of transporters and enzymes”. Cyclosporine A (CsA) is an inhibitor of OATPs, P-gp, MRP2, BCRP and CYP3As. Drug–drug interaction (DDI) of CsA with victim drugs occurs via disordering interplay of transporters and enzymes. We aimed to establish a whole-body physiologically-based pharmacokinetic (PBPK) model which predicts disposition of CsA and nine victim drugs including atorvastatin, cerivastatin, pravastatin, rosuvastatin, fluvastatin, simvastatin, lovastatin, repaglinide and bosentan, as well as drug–drug interactions (DDIs) of CsA with nine victim drugs to investigate the integrated effect of enzymes and transporters in liver, intestinal and kidney on drug disposition. Predictions were compared with observations. Most of the predictions were within 0.5–2.0 folds of observations. Atorvastatin was represented to investigate individual contributions of transporters and CYP3As to atorvastatin disposition and their integrated effect. The contributions to atorvastatin disposition were hepatic OATPs >> hepatic CYP3A > intestinal CYP3As ≈ efflux transporters (P-gp/BCRP/MRP2). The results got the conclusion that the developed PBPK model characterizing the interplay of enzymes and transporters was successfully applied to predict the pharmacokinetics of 10 OATP substrates and DDIs of CsA with 9 victim drugs.
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影响因子：
3.4
作者：
Cetkovic, Zora;Cvijic, Sandra;Vasiljevic, Dragana
通讯作者：
Vasiljevic, Dragana
影响因子：
7.3
作者：
Fahrmayr, C.;Koenig, J.;Fromm, M. F.
通讯作者：
Fromm, M. F.
影响因子：
11.1
作者：
Gullestad, L;Nordal, KP;Simonsen, S
通讯作者：
Simonsen, S
影响因子：
4.5
作者：
de la Pena, Amparo;Cui, Xuewei;Loghin, Corina
通讯作者：
Loghin, Corina
影响因子：
1.8
作者：
Fujino, H;Saito, T;Sakaeda, T
通讯作者：
Sakaeda, T