Pretreatment With Rifampicin and Tyrosine Kinase Inhibitor Dasatinib Potentiates the Inhibitory Effects Toward OATP1B1- and OATP1B3-Mediated Transport.
Pretreatment With Rifampicin and Tyrosine Kinase Inhibitor Dasatinib Potentiates the Inhibitory Effects Toward OATP1B1- and OATP1B3-Mediated Transport.
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DOI：
10.1016/j.xphs.2017.03.022
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发表时间：
2017-08
影响因子：
3.8
通讯作者：
Yue W
中科院分区：
文献类型：
--
作者：
Pahwa S;Alam K;Crowe A;Farasyn T;Neuhoff S;Hatley O;Ding K;Yue W
目前的研究确定了利福平（一种有机阴离子转运多肽（OATP）抑制剂）和酪氨酸激酶抑制剂达沙替尼预处理对OATP 1B 1和OATP 1B 3介导的转运的影响，并使用静态R值和基于生理学的动态药代动力学模型评价了达沙替尼的OATP介导的药物相互作用（DDI）潜力。利福平和达沙替尼预处理显著降低了OATP 1B 1和OATP 1B 3介导的转运。利福平预处理也显著降低了[3 H]-匹伐他汀和[3 H]-CCK-8在体外培养的人肝细胞中的蓄积。当前研究表明，在评估利福平预处理效应时，雌酮-3-硫酸酯是一种不如雌二醇-17 β-葡萄糖醛酸苷敏感的OATP 1B 1底物。利福平和达沙替尼预处理使对OATP 1B 1的抑制常数（Ki）值分别降低3倍和2.1倍，对OATP 1B 3的抑制常数（Ki）值分别降低2.4倍和2.1倍。预孵育后的体外利福平Ki值与先前报告的体内Ki估计值相当。模型预测，达沙替尼引起OATP 1B 1和OATP 1B 3介导的DDI的可能性较低。延时共聚焦显微镜显示，利福平和达沙替尼预处理不影响HEK 293-GFP-OATP 1B 1和-OATP 1B 3细胞中绿色荧光蛋白（GFP）-OATP 1B 1和-OATP 1B 3的质膜定位。总之，我们报告了新的发现，即利福平和达沙替尼预处理增强了对OATP 1B 1和OATP 1B 3的抑制作用，而不影响转运蛋白的质膜水平。
Current studies determined the effects of pretreatment with rifampicin, an organic anion-transporting polypeptide (OATP) inhibitor, and the tyrosine kinase inhibitor dasatinib on OATP1B1- and OATP1B3-mediated transport, and to evaluate the OATP-mediated drug-drug interaction (DDI) potential of dasatinib using the static R-value and dynamic physiologically-based pharmacokinetic models. Rifampicin and dasatinib pretreatment significantly decreased OATP1B1- and OATP1B3-mediated transport. Rifampicin pretreatment also significantly decreased [3H]-pitavastatin and [3H]-CCK-8 accumulation in human sandwich-cultured hepatocytes. Current studies revealed that estrone-3-sulfate is a less sensitive OATP1B1 substrate than estradiol-17β-glucuronide in assessing rifampicin pretreatment effects. Pretreatment with rifampicin and dasatinib reduced the inhibition constant (Ki) values against OATP1B1 by 3 and 2.1 fold and toward OATP1B3 by 2.4 and 2.1 fold, respectively. The in vitro rifampicin Ki values following pre-incubation are comparable to the estimated in vivo Ki reported previously. Models predict that dasatinib has a low potential to cause OATP1B1- and OATP1B3-mediated DDIs. Time-lapse confocal microscopy demonstrated that rifampicin and dasatinib pretreatment did not affect plasma membrane localization of green-fluorescent protein (GFP)-OATP1B1 and -OATP1B3 in HEK293-GFP-OATP1B1 and -OATP1B3 cells. In summary, we report novel findings that pretreatment with rifampicin and dasatinib potentiates the inhibitory effects toward OATP1B1 and OATP1B3 without affecting plasma membrane levels of the transporters.
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