Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors.

Varun Khurana, Mukul Minocha, Dhananjay Pal, Ashim K Mitra
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引用次数: 37

Abstract

Background: The metabolism of tyrosine kinase inhibitors (TKIs) is mainly mediated via hepatic route, but the mechanism responsible for their hepatocellular accumulation is still unknown. This study was designed to understand the contribution of organic anion transporting polypeptides (OATPs) in the hepatic uptake of selected TKIs - pazopanib, canertinib, erlotinib, vandetanib and nilotinib.

Methods: Michaelis-Menten (MM) kinetic parameters for TKIs were determined by concentration-dependent cellular accumulation of selected TKIs using Chinese hamster ovary cells - wild type as well as transfected with humanized OATP-1B1 and OATP-1B3 transporter proteins.

Results: The MM constant (Km) values of OATP-1B1 for nilotinib and vandetanib are 10.14±1.91 and 2.72±0.25 μM, respectively, and Vmax values of OATP-1B1 for nilotinib and vandetanib were 6.95±0.47 and 75.95±1.99 nmol/mg protein per minute, respectively. Likewise, Km values of OATP-1B3 for canertinib, nilotinib and vandetanib were 12.18±3.32, 7.84±1.43 and 4.37±0.79 μM, respectively, and Vmax values of OATP-1B3 for canertinib, nilotinib and vandetanib were 15.34±1.59, 6.75±0.42 and 194.64±10.58 nmol/mg protein per minute, respectively. Canertinib did not exhibit any substrate specificity toward OATP-1B1. Also, erlotinib and pazopanib did not exhibit any substrate specificity toward OATP-1B1 and -1B3.

Conclusions: Because selected TKIs are the substrates of OATP-1B1 and -1B3 expressed in hepatic tissue, these compounds can be regarded as molecular targets for transporter-mediated drug-drug interactions (DDIs). Any alteration in the function of these hepatic OATPs might account for the pharmacokinetic variability of TKIs.

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ooatp - 1b1和/或ooatp - 1b3在酪氨酸激酶抑制剂肝脏配置中的作用。
背景:酪氨酸激酶抑制剂(tyrosine kinase inhibitors, TKIs)的代谢主要通过肝脏途径介导,但其在肝细胞积累的机制尚不清楚。本研究旨在了解有机阴离子转运多肽(OATPs)在肝脏摄取选定的TKIs -帕唑帕尼、卡尼替尼、厄洛替尼、万德替尼和尼洛替尼中的作用。方法:利用野生型中国仓鼠卵巢细胞,转染人源化OATP-1B1和OATP-1B3转运蛋白,采用浓度依赖性细胞积累法测定TKIs的Michaelis-Menten (MM)动力学参数。结果:ooatp - 1b1对尼洛替尼和万德替尼的MM常数(Km)分别为10.14±1.91和2.72±0.25 μM, Vmax分别为6.95±0.47和75.95±1.99 nmol/mg protein / min。同样,卡尼替尼、尼洛替尼和万德替尼的otp - 1b3的Km值分别为12.18±3.32、7.84±1.43和4.37±0.79 μM,卡尼替尼、尼洛替尼和万德替尼的Vmax值分别为15.34±1.59、6.75±0.42和194.64±10.58 nmol/mg protein / min。卡奈替尼对otp - 1b1没有任何底物特异性。此外,厄洛替尼和帕唑帕尼对otp - 1b1和-1B3没有表现出任何底物特异性。结论:由于选定的TKIs是肝组织中ooatp - 1b1和-1B3表达的底物,这些化合物可被视为转运体介导的药物-药物相互作用(ddi)的分子靶点。这些肝脏oops功能的任何改变都可能解释TKIs的药代动力学变异性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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