BACKGROUND & AIMS:
:The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.
背景与目标:
胆汁盐输出泵(BSEP)在肝细胞的小管结构域表达,是消除单价胆汁酸(BAs)进入胆管的主要途径。发现最令人信服的证据是,BA转运功能障碍与人类肝损伤有关,且携带的突变携带者使BSEP无法起作用。根据越来越多的证据,药物诱发的BSEP干扰与人类肝损伤之间似乎存在很强的联系。但是,因果关系尚未建立。因此,最好将药物诱导的BSEP干扰视为肝损伤的易感因素,因为其他与宿主或药物相关的特性可能会导致肝毒性的发展。为了更好地理解BSEP干扰与人类肝损伤之间的关系,在表达BSEP的膜囊泡中评估了600多种市售或撤回的药物。还描述了在1期人体试验中失败的化合物的示例,即AMG009。AMG009显示了临床前安全性研究未预测到的人类肝损伤的证据,并暗示了BSEP抑制作用。对于109种对体外BSEP功能有一定影响的药物,注明了临床用途,与肝毒性的关系,药代动力学数据和其他信息。估计每种带注释药物的稳态浓度(C(ss)),并计算该值与测得的IC 50效能值之间的比率,以尝试将暴露与体外效能联系起来。当考虑暴露时,C(ss)/ BSEPIC₅₀比≥0.1的95%的带注释化合物与某种形式的肝损伤有关。然后,我们调查了肝损伤的临床证据与对多药耐药相关蛋白(MRP)的影响之间的关系,这些蛋白在BA动态平衡中起作用。还通过膜囊泡试验评估了600种药物对MRP2,MRP3和MRP4功能的影响。 C(ss)/ BSEPIC₅₀比≥0.1和C(ss / MRPIC₅₀比≥0.1)与人类肝损伤的某些证据几乎具有100%的相关性。这些数据表明,暴露数据的整合以及对BSEP以及一个或多个MRP的影响的了解,是一种有用的工具,可用于告知由于BA运输改变而引起肝损伤的可能性。