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首页> 外文期刊>Journal of applied toxicology >Liver safety evaluation of endothelin receptor antagonists using HepatoPac ? ? : A single model impact assessment on hepatocellular health, function and bile acid disposition
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Liver safety evaluation of endothelin receptor antagonists using HepatoPac ? ? : A single model impact assessment on hepatocellular health, function and bile acid disposition

机译：使用肝缺陷的内皮素受体拮抗剂的肝脏安全评估？ 还 ：对肝细胞健康，功能和胆汁酸性分化的单一模型影响评估

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Abstract Marketed (bosentan, ambrisentan) and discontinued (sitaxsentan, CI1034) endothelin receptor antagonists were examined in the human micropatterned hepatocyte coculture (MPCC) model HepatoPac?. Differences across hepatocellular health (cellular adenosine triphosphate/glutathione content), function (urea production/albumin secretion) and taurocholic acid transport (biliary clearance/excretion index) were compared using amiodarone and ciclosporin A as positive controls. Ambrisentan had the weakest potency in all six endpoints, while sitaxsentan, bosentan and CI1034 had more potent effects on hepatobiliary transport than health/function endpoints. Normalization to clinicalC max gave the following relative rank order of safety based on margins for each endpoint: ambrisentan爀 CI1034爚燽osentan?爏itaxsentan. These data suggested impaired hepatobiliary disposition might contribute to a more prominent role in liver injury associated within sensitive human populations exposed to these compounds than direct hepatocellular toxicity. Rat, dog and monkey MPCCs also showed greater sensitivity potential to disrupted hepatobiliary disposition compared with hepatocellular health/functional endpoints. Drug metabolism competency was exhibited across all species. In vivo, rats and dogs appear more resistant to transaminase elevations and/or histological evidence of liver injury caused by these mechanisms even at exceedingly high systemic exposures relative to sensitive humans. Rats and dogs are resistant to hepatobiliary toxicants due to physiological differences in bile composition/handling. Although traditional animal testing provides adequate safety coverage for advancement of novel pharmaceuticals into clinical trials, supplemental assays employing human MPCCs may strengthen weightofevidence predictions for sensitive human populations. Proving the predictive value of this single impact assessment model in advance of clinical trial information for human liver injury risk is needed across more pharmaceuticals.
机译：摘要销售（波斯坦坦，Ambrisentan）和停止（Sitaxsentan，CI1034）内皮素受体拮抗剂在人类的微型解放肝细胞共培养（MPCC）模型肝孔中进行了检查？使用胺碘酮和Ci​​closporinA作为阳性对照进行肝细胞健康（细胞腺苷三磷酸盐/谷胱甘肽含量），功能（尿素产生/白蛋白分泌）和牛磺酸酸输送（胆量间隙/排泄物）的差异。 Ambrisentan在所有六个终点中具有最弱的效力，而Syaxsentan，Bosentan和Ci1034对肝胆道运输具有比健康/功能终点更有效的影响。基于每个端点的边距，临床CLAM MAX的归一化为以下的相对等级排序顺序：Ambrisentan爀CI1034爚燽Osentan？GT;爏itaxsentan。这些数据表明，肝胆胆水位受损可能导致肝损伤中的肝脏损伤在暴露于这些化合物的敏感人群中，而不是直接肝细胞毒性。与肝细胞健康/功能终点相比，大鼠，狗和猴子MPCCs还表现出更大的敏感性潜力来破坏肝胆处理。在所有物种上展出了药物代谢能力。在体内，大鼠和狗显得更耐药升高和/或肝损伤的组织学证据，甚至在相对于敏感人类的极高的全身曝光，甚至是这些机制的肝损伤。由于胆汁成分/处理的生理差异，大鼠和狗对肝胆毒性有抗性。虽然传统的动物测试提供了足够的安全覆盖，用于推进新型药物转化为临床试验，雇用人体MPCC的补充测定可以加强对敏感人群的权力预测。在更多药品中，在更多药物中，在临床试验信息之前提前证明了这种单一影响评估模型的预测值。

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