Assessing OATP1B1- and OATP1B3-Mediated Drug-Drug Interaction Potential of Vemurafenib Using R-Value and Physiologically-Based Pharmacokinetic Models.
Assessing OATP1B1- and OATP1B3-Mediated Drug-Drug Interaction Potential of Vemurafenib Using R-Value and Physiologically-Based Pharmacokinetic Models.
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DOI：
10.1016/j.xphs.2020.06.016
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发表时间：
2021-01
影响因子：
3.8
通讯作者：
Yue W
中科院分区：
文献类型：
--
作者：
Kayesh R;Farasyn T;Crowe A;Liu Q;Pahwa S;Alam K;Neuhoff S;Hatley O;Ding K;Yue W
有机阴离子转运多肽 (OATP) 1B1 和 OATP1B3 是转运蛋白介导的药物相互作用 (DDI) 的重要决定因素。目前的研究使用 R 值和基于生理学的药代动力学 (PBPK) 模型评估了 Vemurafenib（一种具有高蛋白结合和低水溶性的激酶抑制剂药物）的 OATP1B1 和 OATP1B3 介导的 DDI 潜力。在转运蛋白过表达的人胚肾 293 稳定细胞系中的 100% 人血浆中测定了威罗非尼对 OATP1B1 和 OATP1B3 的总半最大抑制浓度（IC50，总）值。通过快速平衡透析测定加入摄取测定板（fu，血浆，inc）之前（fu，血浆）和之后人血浆中维罗非尼的未结合分数。 fu,plasma 与 fu,plasma,inc 之间无统计学差异。维莫非尼针对 OATP1B1 和 OATP1B3 的 IC50 总值分别为 175 ± 82 和 231 ± 26 μM。然后将 R 值 [R = 1 + fu,plasma × Iin,max/(fu,plasma,inc × IC50,total)] 简化为 R=1+Iin,max/IC50,total，并且 OATP1B1 和 OATP1B3 分别为 1.76 和 1.57。与单独使用普伐他汀相比，稳态时单剂量普伐他汀（40 mg）与维莫非尼（960 mg，每日两次）共同给药时模拟的普伐他汀 AUC 值为 1.28。 R 值和 PBPK 模型都预测维莫非尼有可能引起 OATP1B1 和 OATP1B3 介导的 DDI。
Organic anion transporting polypeptides (OATP) 1B1 and OATP1B3 are important determinants of transporter-mediated drug-drug interactions (DDIs). Current studies assessed the OATP1B1 and OATP1B3-mediated DDI potential of vemurafenib, a kinase inhibitor drug with high protein binding and low aqueous solubility, using R-value and physiologically based pharmacokinetic (PBPK) models. The total half-maximal inhibitory concentration (IC50,total) values of vemurafenib against OATP1B1 and OATP1B3 were determined in 100% human plasma in transporter-overexpressing human embryonic kidney 293 stable cell lines. The unbound fraction of vemurafenib in human plasma before (fu,plasma) and after addition into the uptake assay plate (fu,plasma,inc) were determined by rapid equilibrium dialysis. There was no statistically significant difference between fu,plasma and fu,plasma,inc. Vemurafenib IC50,total values against OATP1B1 and OATP1B3 are 175 ± 82 and 231 ± 26 μM, respectively. The R-values [R = 1 + fu,plasma × Iin,max/(fu,plasma,inc × IC50,total)] were then simplified as R=1+Iin,max/IC50,total, and were 1.76 and 1.57 for OATP1B1 and OATP1B3, respectively. The simulated pravastatin AUC ratio was 1.28 when a single dose of pravastatin (40 mg) was co-administered with vemurafenib (960 mg, twice daily) at steady-state, compared to pravastatin alone. Both R-value and PBPK models predict that vemurafenib has the potential to cause OATP1B1- and OATP1B3-mediated DDIs.
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影响因子：
4.8
作者：
König, J;Cui, YH;Keppler, D
通讯作者：
Keppler, D
DOI：
10.1002/jbm.820030114
发表时间：
1969-03-01
期刊：
Journal of biomedical materials research
影响因子：
--
作者：
Brash, J L;Lyman, D J
通讯作者：
Lyman, D J
影响因子：
3.8
作者：
Farasyn, Taleah;Crowe, Alexandra;Yue, Wei
通讯作者：
Yue, Wei
影响因子：
3.7
作者：
Gertz, Michael;Cartwright, Catherine M.;Galetin, Aleksandra
通讯作者：
Galetin, Aleksandra
影响因子：
1.8
作者：
Kikuchi, Ryota;Peterkin, Vincent C.;Bow, Daniel A. J.
通讯作者：
Bow, Daniel A. J.