Ileal Bile Acid Transporter Inhibition for the Treatment of Chronic Constipation, Cholestatic Pruritus, and NASH

Abstract

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.

Boiogito prevents dietary lithocholic acid (LCA)‐induced cholestatic liver injury through the suppression of intestinal LCA absorption

“…). The conjugated forms of bile acids are absorbed mainly in the ileum through active transporters such as the apical sodium‐dependent bile acid transporter (ASBT) . Neither dietary LCA, nor BOT–LCA co‐treatment, however, significantly decreased the expression of ASBT in the intestine (Figure S2).…”

Bile Acid Receptor Therapeutics Effects on Chronic Liver Diseases

“…During normal enterohepatic circulation, IBAT/ASBT is responsible for the reabsorption of BAs in the intestinal tract prior to secretion into the portal blood system (75). Additionally, ASBT is responsible for cholehepatic shunting of BAs between cholangiocytes and hepatocytes, which ultimately increases hepatic BA pool.…”

“…to increased BA deposition (75). IBAT/ASBT inhibitors are potential therapeutic candidates for this detrimental symptom (76).…”

Future Medical Treatment of PSC

“…The apical sodium-dependent bile acid transporter (ASBT) is pivotal for reabsorption of conjugated bile acids in the ileum [93]. Pharmacological inhibition of ileal ASBT with nonabsorbable ASBT inhibitors, so-called IBAT (ileal bile acid transporter) inhibitors, leads to a lower bile acid pool, which is associated with improved liver histology in animal models of cholestatic liver disease and NASH [93]. In cholestatic liver diseases with pruritus, the interruption of the enterohepatic circulation of bile acids with IBAT inhibitors showed promising effects on cholestatic pruritus.…”

“…In cholestatic liver diseases with pruritus, the interruption of the enterohepatic circulation of bile acids with IBAT inhibitors showed promising effects on cholestatic pruritus. However, at least in adults, moderate to severe abdominal side effects substantially limit their application [93]. The ASBT inhibitor maralixibat (CAMEO; NCT02061540) has already been tested in 27 patients with PSC.…”