Measures of BSEP Inhibition In Vitro Are Not Useful Predictors of DILI
Measures of BSEP Inhibition In Vitro Are Not Useful Predictors of DILI
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DOI：
10.1093/toxsci/kfx284
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发表时间：
2018-04-01
影响因子：
3.8
通讯作者：
Benet, Leslie Z.
中科院分区：
文献类型：
--
作者：
Chan, Rosa;Benet, Leslie Z.
药物抑制胆盐输出泵（BSEP）已被认为是药物可能引起药物性肝损伤（DILI）的危险因素，并被认为是导致DILI的重要机制。对于多种药物，已经观察到体外抑制BSEP的效力与其在人体内引起DILI的倾向之间的相关性。这些发现被解释为BSEP抑制可能是帮助解释某些药物如何引发DILI的重要机制。由于生物制药药物处置分类系统（BDDCS）可以用于描述和预测一些重要的转运蛋白在药物-药物相互作用方面的作用，我们评估了BDDCS提供的信息，以了解BSEP的抑制倾向。在这里，我们分析了一种化合物抑制BSEP功能的能力与导致人类肝损伤之间的关系，使用了已发表的DILI数据集的汇编，这些数据集筛选了BSEP抑制剂、其他肝脏转运蛋白和其他基于机制的毒性关键事件。我们的结果表明，体外BSEP抑制是普遍预测DILI的支持很少。相反，我们表明，最有效的BSEP抑制剂是BDDCS 2类药物，我们之前已经证明，这是最可能与DILI相关的BDDCS类别。由于BDDCS类别与任何提出的DILI机制假设无关，我们认为，如果BSEP单独抑制或与其他转运体抑制的测量不能与2类分配区分开来，则不支持体外BSEP抑制可预测DILI。
Inhibition of the bile salt export pump (BSEP) by a drug has been implicated as a risk factor for a drug's potential to cause drug-induced liver injury (DILI) and is thought to be an important mechanism leading to DILI. For a wide variety of drugs a correlation has been observed between the potency of in vitro BSEP inhibition and its propensity to cause DILI in humans. These findings were interpreted to suggest that BSEP inhibition could be an important mechanism to help explain how some drugs initiate DILI. Because the Biopharmaceutics Drug Disposition Classification System (BDDCS) can be useful in characterizing and predicting some important transporter effects in terms of drug-drug interactions, we evaluated the information provided by BDDCS in order to understand the inhibition propensity of BSEP. Here we analyze the relationship between a compound's ability to inhibit BSEP function and cause liver injury in humans using a compilation of published DILI datasets that have screened for BSEP inhibitors, other hepatic transporters and other mechanism-based toxicity key events. Our results demonstrate that there is little support for in vitro BSEP inhibition being universally DILI predictive. Rather we show that most potent BSEP inhibitors are BDDCS class 2 drugs, which we have demonstrated previously is the BDDCS class most likely to be DILI related. Since BDDCS class is not related to any proposed DILI mechanistic hypotheses, we maintain that if measures of BSEP inhibition alone or together with inhibition of other transporters cannot be differentiated from class 2 assignment, there is no support for in vitro BSEP inhibition being DILI predictive.