Purpose

The involvement of the intestinally expressed xenobiotic transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) have been implicated in apixaban disposition based on in vitro studies. Recommendations against co-administration of apixaban with inhibitors of these efflux transporters can be found throughout the literature as well as in the apixaban FDA label. However, the clinical relevance of such findings is questionable due to the high permeability and high solubility characteristics of apixaban.

Methods

Using recently published methodologies to discern metabolic- from transporter- mediated drug-drug interactions, a critical evaluation of all published apixaban drug-drug interaction studies was conducted to investigate the purported clinical significance of efflux transporters in apixaban disposition.

Results

Rational examination of these clinical studies using basic pharmacokinetic theory does not support the clinical significance of intestinal efflux transporters in apixaban disposition. Further, there is little evidence that efflux transporters are clinically significant determinants of systemic clearance.

Conclusions

Inhibition or induction of intestinal CYP3A4 can account for exposure changes of apixaban in all clinically significant drug-drug interactions, and lack of intestinal CYP3A4 inhibition can explain all studies with no exposure changes, regardless of the potential for these perpetrators to inhibit intestinal or systemic efflux transporters.

中文翻译：

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肠外排转运蛋白 P-gp 和 BCRP 在阿哌沙班处置中没有临床意义

目的

基于体外研究，肠道表达的异生物质转运蛋白 P-糖蛋白 (P-gp) 和乳腺癌抗性蛋白 (BCRP) 的参与与阿哌沙班处置有关。反对将阿哌沙班与这些外排转运蛋白抑制剂共同给药的建议可以在整个文献以及阿哌沙班 FDA 标签中找到。然而，由于阿哌沙班的高渗透性和高溶解度特性，这些发现的临床相关性值得怀疑。

方法

使用最近发表的方法来辨别代谢-与转运蛋白介导的药物-药物相互作用，对所有已发表的阿哌沙班药物-药物相互作用研究进行了批判性评估，以研究外排转运蛋白在阿哌沙班处置中的所谓临床意义。

结果

使用基本药代动力学理论对这些临床研究进行的合理检查不支持阿哌沙班处置中肠外排转运蛋白的临床意义。此外，几乎没有证据表明外排转运蛋白是全身清除的临床重要决定因素。

结论

肠道 CYP3A4 的抑制或诱导可以解释阿哌沙班在所有临床上显着的药物相互作用中的暴露变化，而肠道 CYP3A4 抑制的缺乏可以解释所有没有暴露变化的研究，无论这些肇事者抑制肠道或全身外排的潜力如何运输者。