Obeticholic Acid: An Update of Its Pharmacological Activities in Liver Disorders
Obeticholic Acid: An Update of Its Pharmacological Activities in Liver Disorders
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DOI：
10.1007/164_2019_227
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发表时间：
2019-01-01
期刊：
影响因子：
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通讯作者：
Distrutti, Eleonora
中科院分区：
文献类型：
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作者：
Fiorucci, Stefano;Di Giorgio, Cristina;Distrutti, Eleonora
乙酰胆酸(OCA)，6a-乙基-3a，7a-二羟基-5-胆烷-24-OIC酸，是鹅去氧胆酸(CDCA，3α，7-α-二羟基-5-胆烷-24-OIC酸)的半合成衍生物。鹅去氧胆酸是由胆固醇在肝脏中合成的一种相对疏水的初级胆汁酸。OCA，也被称为6-乙基-CDCA或INT-747，最初是由佩鲁贾大学的研究人员在2002年描述的，作为胆汁酸传感器法尼醇-X受体(FXR)的选择性配体。除FXR外，与CDCA类似，OCA还激活GPBAR1/TGR5，这是一种细胞膜G蛋白偶联的次级胆汁酸受体。2016年，根据显示在降低血浆碱性磷酸酶水平方面有效的第二阶段研究结果，OCA已获准作为对UDCA无效的PBC患者的二线治疗。碱性磷酸酶是原发性胆管炎(PBC)疾病进展的替代生物标志物。OCA在PBC患者中的使用与几种副作用有关，其中最常见的是瘙痒，其发生率呈剂量依赖关系，当该药作为单一疗法使用时，其发生率极高。此外，OCA的使用增加了肝硬变PBC患者发生肝功能衰竭的风险。目前，OCA正在研究其在治疗非酒精性脂肪性肝炎(NASH)方面的潜力。II期和III期试验表明，OCA可能会减轻NASH患者的肝纤维化严重程度，但它在逆转疾病的脂肪变性成分方面没有效果，但降低了循环中的高密度脂蛋白-C水平，增加了低密度脂蛋白-C。总而言之，OCA是第一个进入临床阶段的FXR配体，现在正进入其生命的第三个十年，突出了与FXR靶向治疗相关的潜在好处和风险。
Obeticholic acid (OCA), 6a-ethyl-3a,7a-dihydroxy-5-cholan-24-oic acid, is a semisynthetic derivative of the chenodeoxycholic acid (CDCA, 3 alpha,7-alpha-dihydroxy-5-cholan-24-oic acid), a relatively hydrophobic primary bile acid synthesized in the liver from cholesterol. OCA, also known as 6-ethyl-CDCA or INT-747, was originally described by investigators at the Perugia University in 2002 as a selective ligand for the bile acid sensor, farnesoid-X-receptor (FXR). In addition to FXR and similarly to CDCA, OCA also activates GPBAR1/TGR5, a cell membrane G protein-coupled receptor for secondary bile acids. In 2016, based on the results of phase II studies showing efficacy in reducing the plasma levels of alkaline phosphatase, a surrogate biomarker for disease progression in primary biliary cholangitis (PBC), OCA has gained approval as a second-line treatment for PBC patients nonresponsive to UDCA. The use of OCA in PBC patients associates with several side effects, the most common of which is pruritus, whose incidence is dose-dependent and is extremely high when this agent is used as a monotherapy. Additionally, the use of OCA associates with the increased risk for the development of liver failure in cirrhotic PBC patients. Currently, OCA is investigated for its potential in the treatment of nonalcoholic steatohepatitis (NASH). Phase II and III trials have shown that OCA might attenuate the severity of liver fibrosis in patients with NASH, but it has no efficacy in reversing the steatotic component of the disease, while reduces the circulating levels of HDL-C and increases LDL-C. In summary, OCA has been the first-in-class of FXR ligands advanced to a clinical stage and is now entering its third decade of life, highlighting the potential benefits and risk linked to FXR-targeted therapies.