Purpose

The involvement of the intestinally expressed xenobiotic transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) have been implicated in rivaroxaban disposition based on in vitro studies, similar to what had previously been proposed for apixaban. We recently showed that these efflux transporters were not clinically relevant for apixaban disposition and examine here their relevance for this second Factor Xa inhibitor.

Methods

Using recently published methodologies to discern metabolic- from transporter- mediated drug interactions, a critical evaluation was undertaken of 9 rivaroxaban studies reporting 12 DDIs, one study of food effects and one study of hepatic function.

Results

Rationale examination of these clinical studies using basic pharmacokinetic theory finds little support for the clinical significance of intestinal efflux transporters in rivaroxaban disposition. Drug-drug interactions are most likely adequately predicted based on the level of CYP 3A metabolism.

Conclusion

These analyses indicate that inhibition of efflux transporters appears to have negligible, clinically insignificant effects on the rivaroxaban absorption process, which is consistent with the concern that predictions based on in vitro measures may not translate to a clinically relevant interaction in vivo. We emphasize the need to evaluate gastric emptying, dissolution and other processes related to absorption when using MAT changes to indicate efflux transporter inhibition.

中文翻译：

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通过检查吸收变化研究肠道转运蛋白参与利伐沙班处置

目的

基于体外研究，肠道表达的外源性转运蛋白 P-糖蛋白 (P-gp) 和乳腺癌耐药蛋白 (BCRP) 与利伐沙班处置有关，类似于之前对阿哌沙班提出的建议。我们最近表明，这些外排转运蛋白与阿哌沙班处置没有临床相关性，并在此检查它们与第二种 Xa 因子抑制剂的相关性。

方法

使用最近发表的方法来区分代谢与转运蛋白介导的药物相互作用，对报告 12 项 DDI 的 9 项利伐沙班研究、一项关于食物影响的研究和一项关于肝功能的研究进行了严格评估。

结果

使用基本药代动力学理论对这些临床研究进行的基本原理检查几乎没有支持肠道外排转运蛋白在利伐沙班处置中的临床意义。基于 CYP 3A 代谢水平很可能充分预测药物-药物相互作用。

结论

这些分析表明，外排转运蛋白的抑制似乎对利伐沙班吸收过程具有可忽略不计的临床影响，这与基于体外测量的预测可能无法转化为体内临床相关相互作用的担忧是一致的。我们强调，当使用MAT变化来指示外排转运蛋白抑制时，需要评估胃排空、溶解和其他与吸收相关的过程。