Contribution of ABCC4-mediated gastric transport to the absorption and efficacy of dasatinib.
Contribution of ABCC4-mediated gastric transport to the absorption and efficacy of dasatinib.
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DOI：
10.1158/1078-0432.ccr-13-0980
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发表时间：
2013-08-15
期刊：
影响因子：
--
通讯作者：
Baker SD
中科院分区：
文献类型：
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作者：
Furmanski BD;Hu S;Fujita KI;Li L;Gibson AA;Janke LJ;Williams RT;Schuetz JD;Sparreboom A;Baker SD
已知几种口服多激酶抑制剂在体外与人ATP结合盒转运蛋白ABCC 4（MRP 4）相互作用，但这种相互作用的体内相关性仍然知之甚少。我们假设宿主ABCC 4活性可能影响达沙替尼的药代动力学特征，并随后影响其抗肿瘤特性。在转染人ABCC 4或直系同源小鼠转运蛋白Abcc 4的细胞中研究了达沙替尼的转运。在野生型和Abcc 4缺失小鼠中进行药代动力学研究。在Ph+急性淋巴细胞白血病（ALL）模型中，通过注射表达p185（BCR-ABL）的Arf（−/−）前B细胞，评价了Abcc 4缺陷对达沙替尼疗效的影响。与对照细胞相比，在过表达ABCC 4或Abcc 4的细胞中达沙替尼积累显著改变（P<0.001）。体内Abcc 4缺乏与口服达沙替尼全身暴露量降低1.75倍相关，但对静脉注射达沙替尼的药代动力学没有影响。发现Abcc 4在胃中高度表达，Abcc 4缺陷会损害离体小鼠胃中达沙替尼的外排（P<0.01），而胃pH值无任何可检测的变化。基于生物发光成像，接受达沙替尼的Abcc 4缺失小鼠的白血病负荷增加，与野生型小鼠相比，总生存率降低（P=0.048）。这项研究表明，胃中的Abcc 4促进了达沙替尼的口服吸收，它可能对其他口服底物（如乙酰水杨酸）起着类似的作用。这种现象也为胃切除术后某些药物的吸收不良提供了一种机制解释。
Several oral multikinase inhibitors are known to interact in vitro with the human ATP-binding cassette transporter ABCC4 (MRP4), but the in vivo relevance of this interaction remains poorly understood. We hypothesized that host ABCC4 activity may influence the pharmacokinetic profile of dasatinib and subsequently affect its antitumor properties. Transport of dasatinib was studied in cells transfected with human ABCC4 or the ortholog mouse transporter, Abcc4. Pharmacokinetic studies were done in wildtype and Abcc4-null mice. The influence of Abcc4-deficiency on dasatinib efficacy was evaluated in a model of Ph+ acute lymphoblastic leukemia (ALL) by injection of luciferase-positive, p185(BCR-ABL)-expressing Arf(−/−) pre-B cells. Dasatinib accumulation was significantly changed in cells over-expressing ABCC4 or Abcc4 compared to control cells (P<0.001). Deficiency of Abcc4 in vivo was associated with a 1.75-fold decrease in systemic exposure to oral dasatinib, but had no influence on the pharmacokinetics of i.v. dasatinib. Abcc4 was found to be highly expressed in the stomach, and dasatinib efflux from isolated mouse stomachs ex vivo was impaired by Abcc4-deficiency (P<0.01), without any detectable changes in gastric pH. Abcc4-null mice receiving dasatinib had an increase in leukemic burden, based on bioluminescence imaging, and decreased overall survival compared to wildtype mice (P=0.048). This study suggests that Abcc4 in the stomach facilitates the oral absorption of dasatinib, and it possibly plays a similar role for other orally-administered substrates, such as acetylsalicylic acid. This phenomenon also provides a mechanistic explanation for the malabsorption of certain drugs following gastric resection.