Al-Dury Samer, Marschall Hanns-Ulrich
Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
Front Pharmacol. 2018 Aug 21;9:931. doi: 10.3389/fphar.2018.00931. eCollection 2018.
Bile acids are synthesized from cholesterol in the liver, excreted with bile into the duodenum, almost completely taken up again in the distal ileum and finally returned to the liver with portal blood in a process termed enterohepatic circulation. Bile acid synthesis, excretion, and reuptake are tightly regulated. The apical sodium-dependent bile acid transporter [ASBT; also known as ileal bile acid transporter (IBAT) and SLC10A2] is pivotal for the almost complete reabsorption of conjugated bile acids in the ileum. Dysfunctional IBAT may be the cause of bile acid diarrhea. Pharmacological IBAT inhibition results in an increased bile acid load in the colon and subsequently a lower bile acid pool, which is associated with improved liver histology in animal models of cholestatic liver disease and non-alcoholic steatohepatitis (NASH). In humans, IBAT inhibitors have been tested in clinical trials with widely different indications: in patients with idiopathic chronic constipation, an increased number of bowel movements was observed. In adult and pediatric cholestatic liver diseases with pruritus, various IBAT inhibitors showed potential to improve itching. Adverse events of IBAT inhibitors, based on their mode of action, are abdominal pain and diarrhea which might patients to withdraw from study medications. So far, no data are available of a study of IBAT inhibitors in patients with NASH. In this review we summarize the preclinical and most recent clinical studies with various IBAT inhibitors and discuss the difficulties that should be addressed in future studies.
胆汁酸在肝脏中由胆固醇合成，随胆汁排入十二指肠，几乎在回肠末端被完全重吸收，最终通过肠肝循环经门静脉血回到肝脏。胆汁酸的合成、排泄和重吸收受到严格调控。顶端钠依赖性胆汁酸转运体[ASBT；也称为回肠胆汁酸转运体(IBAT)和SLC10A2]对于回肠中结合胆汁酸的几乎完全重吸收至关重要。IBAT功能异常可能是胆汁酸腹泻的原因。药理学上抑制IBAT会导致结肠中胆汁酸负荷增加，进而使胆汁酸池减少，这与胆汁淤积性肝病和非酒精性脂肪性肝炎(NASH)动物模型中肝脏组织学改善有关。在人类中，IBAT抑制剂已在具有广泛不同适应症的临床试验中进行了测试：在特发性慢性便秘患者中，观察到排便次数增加。在患有瘙痒的成人和儿童胆汁淤积性肝病中，各种IBAT抑制剂显示出改善瘙痒的潜力。基于其作用方式，IBAT抑制剂的不良事件是腹痛和腹泻，这可能会使患者退出研究用药。到目前为止，尚无关于NASH患者使用IBAT抑制剂的研究数据。在本综述中，我们总结了各种IBAT抑制剂的临床前和最新临床研究，并讨论了未来研究中应解决的困难。
