[The inhibitors of the apical sodium-dependent bile acid transporter (ASBT) as promising drugs]. / Ingibitory natrii-zavisimogo perenoschika zhelchnykh kislot (ASBT) kak perspektivnye lekarstvennye sredstva.

Inhibition of the apical sodium-dependent bile acid transporter (ASBT, also known as IBAT - ileal bile acid transporter, SLC10A2) leads to disruption of the enterohepatic circulation of bile acids and their excretion with fecal masses. This is accompanied by cholesterol utilization for synthesis of new bile acids. ASBT inhibitors are promising drugs for the treatment of such diseases as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, type 2 diabetes mellitus, necrotic enterocolitis, chronic constipation, atherosclerosis. To date the most known chemically synthesized inhibitors are: A3309, SHP626, A4250, 264W94, GSK2330672, SC-435. All of them are at different stages of clinical trials, which confirm the high efficacy and good tolerance of these inhibitors. Current trends in this field also include directed chemical synthesis of ASBT inhibitors, as well as their search among substances of plant origin.

Elobixibat, the first-in-class Ileal Bile Acid Transporter inhibitor, for the treatment of Chronic Idiopathic Constipation.

INTRODUCTION: Elobixibat is the first in class ileal bile acid transporter (IBAT) inhibitor. IBAT inhibitors block ileal absorption of bile acids by: (1) interrupting the enterohepatic circulation of bile resulting in a fall in serum cholesterol and (2) increasing the delivery of bile acids into the colon. Increasing colonic bile acids causes mucosal fluid secretion and enhances colonic motor activity. Changes in colonic physiology may be useful in treating constipation. Areas covered: In this review, the author reviews the prevalence and medical cost of Chronic Idiopathic Constipation (CIC) and the heterogeneity of the CIC patient population as a complicating factor in drug development and clinical care. He also reviews the history of Bile Acid cathartics and the complex pharmacophysiology of bile therapy with fluid and electrolyte shifts, colonic motor function changes and mucosal immunologic activation. Finally, the author reviews elobixabat development and the clinical trials that demonstrate improvement in constipation. Expert opinion: The early phases of elobixibat development provide confirmation of high IBAT binding affinity which translates into the expected inhibition of enterohepatic bile acid circulation and enhanced delivery of ileal bile acids to the colon associated with expected physiological changes. Elobixibat as a treatment of CIC appears promising.

Elobixibat and its potential role in chronic idiopathic constipation.

Chronic idiopathic constipation is highly prevalent among adults. Bile acids (BAs) and the enterohepatic BA circulation modulate colonic secretion and motility that affect transit. BAs in the colon have a dual action as osmotic and stimulant agents. Newer agents, such as elobixibat (A3309), an inhibitor of the ileal BA transporter, have the potential to improve significantly the management of chronic constipation, with minimal adverse effects. Elobixibat modulates the enterohepatic BA circulation, enhancing the delivery of BAs to the colon where they induce secretory and motor effects. Secondary effects of the inhibition of BA absorption are reduced activation of the farnesoid X receptor, decreased secretion of fibroblast growth factor-19 into the portal circulation, and increased BA synthesis. This review focuses on the role of BAs, the enterohepatic BA circulation, and an ileal BA transporter inhibitor (elobixibat) in chronic constipation.