Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors.
Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors.
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DOI：
10.1515/dmdi-2013-0062
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Mitra AK
中科院分区：
文献类型：
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作者：
Khurana V;Minocha M;Pal D;Mitra AK
酪氨酸激酶抑制剂（TKI）的代谢主要通过肝脏途径介导，但其肝细胞蓄积的机制尚不清楚。本研究旨在了解有机阴离子转运多肽（OATP）在选定TKI（帕唑帕尼、canertinib、厄洛替尼、凡德他尼和尼洛替尼）肝脏摄取中的作用。使用中国仓鼠卵巢细胞-野生型以及人源化OATP-1B 1和OATP-1B 3转运蛋白转染的细胞，通过选定TKI的浓度依赖性细胞蓄积测定TKI的Michaelis-Menten（MM）动力学参数。尼洛替尼和凡德他尼的OATP-1B 1的MM常数（Km）值分别为10.14±1.91和2.72±0.25 μM，尼洛替尼和凡德他尼的OATP-1B 1的Vmax值分别为6.95±0.47和75.95±1.99 nmol/mg蛋白/min。同样，canertinib、尼洛替尼和凡德他尼的OATP-1B 3 Km值分别为12.18±3.32、7.84±1.43和4.37±0.79 μM，canertinib、尼洛替尼和凡德他尼的OATP-1B 3 Vmax值分别为15.34±1.59、6.75±0.42和194.64±10.58 nmol/mg蛋白/min。Canertinib对OATP-1B 1未表现出任何底物特异性。此外，厄洛替尼和帕唑帕尼对OATP-1B 1和-1B3没有表现出任何底物特异性。由于选定的TKI是肝组织中表达的OATP-1B 1和-1B3的底物，因此这些化合物可被视为转运蛋白介导的药物相互作用（DDI）的分子靶点。这些肝脏OATP功能的任何改变都可能导致TKI的药代动力学变异性。
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. 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. 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. 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.