Interference with Bile Salt Export Pump Function Is a Susceptibility Factor for Human Liver Injury in Drug Development
Interference with Bile Salt Export Pump Function Is a Susceptibility Factor for Human Liver Injury in Drug Development
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DOI：
10.1093/toxsci/kfq269
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发表时间：
2010-12-01
影响因子：
3.8
通讯作者：
Hamadeh, Hisham K.
中科院分区：
文献类型：
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作者：
Morgan, Ryan E.;Trauner, Michael;Hamadeh, Hisham K.
胆盐输出泵（BSEP）是一种外排转运蛋白，驱动内源性和外源性底物从肝细胞消除到胆汁中。更具体地说，它负责消除单价结合胆汁盐，很少或没有其他顶端转运蛋白的帮助。已知通过遗传性疾病破坏BSEP活性表现为临床肝损伤，如进行性家族性肝内胆汁淤积症2型。假设药物诱导的BSEP破坏在几种已上市或已撤回治疗药物的肝损伤发生中起作用。不幸的是，临床前动物模型一直是与在人体中观察到的BSEP干扰相关的肝损伤的不良预测因子，这可能是因为胆汁酸组成的种间差异、肝胆转运蛋白调节或组成性表达的差异以及其他机制。因此，BSEP介导的肝脏责任可能直到药物开发的后期才被发现，例如在临床试验期间甚至在许可后。在缺乏BSEP介导的肝损伤的相关临床前试验系统的情况下，可用体外模型对人类健康的毒理学相关性依赖于使用具有已知临床结果的基准化合物，例如上市或撤回的药物。在这项研究中，使用从BSEP转染的昆虫细胞中收获的膜囊泡来评估200多种基准化合物的活性，以彻底研究干扰BSEP功能与肝损伤之间的关系。数据表明，对BSEP功能的药理学干扰与人体肝毒性之间存在相对较强的相关性。尽管最准确的风险翻译将包括药理学效力、药代动力学、清除机制、组织分布、理化性质、适应症和其他药物属性，但对化合物对BSEP干扰的效力的额外理解应有助于限制或避免BSEP相关的人类肝脏责任，这些责任通常无法通过标准临床前动物模型检测到。
The bile salt export pump (BSEP) is an efflux transporter, driving the elimination of endobiotic and xenobiotic substrates from hepatocytes into the bile. More specifically, it is responsible for the elimination of monovalent, conjugated bile salts, with little or no assistance from other apical transporters. Disruption of BSEP activity through genetic disorders is known to manifest in clinical liver injury such as progressive familial intrahepatic cholestasis type 2. Drug-induced disruption of BSEP is hypothesized to play a role in the development of liver injury for several marketed or withdrawn therapeutics. Unfortunately, preclinical animal models have been poor predictors of the liver injury associated with BSEP interference observed for humans, possibly because of interspecies differences in bile acid composition, differences in hepatobiliary transporter modulation or constitutive expression, as well as other mechanisms. Thus, a BSEP-mediated liver liability may go undetected until the later stages of drug development, such as during clinical trials or even postlicensing. In the absence of a relevant preclinical test system for BSEP-mediated liver injury, the toxicological relevance of available in vitro models to human health rely on the use of benchmark compounds with known clinical outcomes, such as marketed or withdrawn drugs. In this study, membrane vesicles harvested from BSEP-transfected insect cells were used to assess the activity of more than 200 benchmark compounds to thoroughly investigate the relationship between interference with BSEP function and liver injury. The data suggest a relatively strong association between the pharmacological interference with BSEP function and human hepatotoxicity. Although the most accurate translation of risk would incorporate pharmacological potency, pharmacokinetics, clearance mechanisms, tissue distribution, physicochemical properties, indication, and other drug attributes, the additional understanding of a compound's potency for BSEP interference should help to limit or avoid BSEP-related liver liabilities in humans that are not often detected by standard preclinical animal models.