(4R)-4-[(3R,5S,6R,7S,8R,9S,10S,13R,14R,17R)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: (4R)-4-[(3R,5S,6R,7S,8R,9S,10S,13R,14R,17R)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid
• 化学式: C₂₆H₄₄O₄
• 分子量: 420.6
• InChiKey: ZXERDUOLZKYMJM-ZLJQTELCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.96
• 拓扑面积：
  77.8
• 氢给体数：
  3
• 氢受体数：
  4

ADMET

毒理性

• 肝毒性

在多项预先注册的临床试验中，奥贝胆酸被发现能显著降低不同肝病患者的血清酶升高比例。没有报道出现肝病恶化或血清ALT或AST进一步增加的情况。然而，奥贝胆酸的产品标签中包含了警告，指出与安慰剂治疗相比，积极治疗时严重肝相关不良事件的发生更为常见。在针对原发性胆汁性胆管炎患者进行的3项安慰剂对照试验的综合分析中，使用10毫克奥贝胆酸的肝相关不良事件发生率为每100患者暴露年5.2次，而安慰剂为2.4次。更高剂量的奥贝胆酸发生率更高：每日25毫克为19.8次每100患者年，每日50毫克为54.5次。这些事件的临床特征、发病时间、酶升高的模式和进展过程并未详细描述。在奥贝胆酸被批准用于治疗原发性胆汁性胆管炎一年多一点后，FDA发布了一封警告信，称他们收到了关于使用奥贝胆酸的患者中19人死亡和11例严重肝损伤的通知，其中大多数但不是所有患者都有预先存在的肝硬化（案例1）。最近，在患有原发性胆汁性胆管炎以及原发性硬化性胆管炎的患者中，严重肝功能衰竭的病例已经报道，这两种疾病都是类似的慢性胆汁淤积性肝病。 在碱性磷酸酶水平正常的患者中，奥贝胆酸治疗与碱性磷酸酶的轻微升高有关，但没有伴随血清转氨酶水平、GGT或胆红素的改变，这表明升高是由于其他来源的碱性磷酸酶（骨骼、胃肠道）。OCA治疗与高达三分之一的患者出现瘙痒有关，但瘙痒的出现或恶化通常不伴随基础肝病的恶化或胆红素或胆酸水平（除OCA外）的增加。因此，奥贝胆酸在改善肝功能测试异常方面具有明显的益处，但与罕见情况下肝病恶化有关，这在预先存在肝硬化的患者中可能具有临床意义，尤其是在使用较高剂量的OCA时。 可能性评分：B（一个罕见但可能导致临床上明显肝损伤的原因，主要发生在预先存在肝硬化的患者中）。

In multiple preregistration clinical trials, obeticholic acid was found to decrease serum enzyme elevations in a high proportion of patients with different liver diseases. Instances of paradoxical worsening of liver disease or further increases in serum ALT or AST were not reported. However, the product label for obeticholic acid includes warnings that serious liver related adverse events occurred more commonly with active therapy than with placebo treatment. In a pooled analysis of 3 placebo controlled trials in patients with primary biliary cholangitis, liver related adverse events were 5.2 per 100 patient exposure years with 10 mg and 2.4 with placebo. Even higher rates occurred with higher doses of obeticholic acid: 19.8 per 100 patient years for 25 mg daily and 54.5 for 50 mg daily. The clinical features, timing of onset, pattern of enzyme elevations and course of these events were not described in detail. Within a little over a year after approval of obeticholic acid as therapy for primary biliary cholangitis, the FDA published a warning letter stating that they had received notification of 19 deaths and 11 cases of severe liver injury in patients taking obeticholic acid, most but not all of whom had preexisting cirrhosis (Case 1). More recently, severe instances of hepatic decompensation have been reported in patients with both primary biliary cholangitis as well as primary sclerosing cholangitis, two similar chronic cholestatic liver diseases. In patients with normal alkaline phosphatase levels, obeticholic therapy is associated with slight elevations in alkaline phosphatase, but without accompanying changes in serum aminotransferase levels, GGT or bilirubin, suggesting that the increases are due to alkaline phosphatase from other sources (bone, gastrointestinal tract). Therapy with OCA has been associated with development of pruritus in up to one-third of patients, but the appearance or worsening of itching is not usually associated with worsening of the underlying liver disease or increase in bilirubin or bile acid levels (other than OCA). Thus, obeticholic acid has apparent beneficial effects on liver test abnormalities, but has been linked to rare instances of worsening liver disease which may have clinical significance in patients with preexisting cirrhosis, particularly with use of higher doses of OCA. Likelihood score: B (a rare but potentially severe cause of clinically apparent liver injury occurring mostly in patients with preexisting cirrhosis).

来源:LiverTox