Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inhibition of ileal bile acid transporter: An emerging therapeutic strategy for chronic idiopathic constipation.

ABSTRACT: Chronic idiopathic constipation is a common disorder of the gastrointestinal tract that encompasses a wide profile of symptoms. Current treatment options for chronic idiopathic constipation are of limited value; therefore, a novel strategy is necessary with an increased effectiveness and safety. Recently, the inhibition of the ileal bile acid transporter has become a promising target for constipation-associated diseases. Enhanced delivery of bile acids into the colon achieves an accelerated colonic transit, increased stool frequency, and relief of constipation-related symptoms. This article provides insight into the mechanism of action of ileal bile acid transporter inhibitors and discusses their potential clinical use for pharmacotherapy of constipation in chronic idiopathic constipation.

SUBMITTER: Mosinska P

PROVIDER: S-EPMC4481438 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Inhibition of ileal bile acid transporter: An emerging therapeutic strategy for chronic idiopathic constipation.

Mosińska Paula P Fichna Jakub J Storr Martin M

World journal of gastroenterology 20150601 24

Chronic idiopathic constipation is a common disorder of the gastrointestinal tract that encompasses a wide profile of symptoms. Current treatment options for chronic idiopathic constipation are of limited value; therefore, a novel strategy is necessary with an increased effectiveness and safety. Recently, the inhibition of the ileal bile acid transporter has become a promising target for constipation-associated diseases. Enhanced delivery of bile acids into the colon achieves an accelerated colo ...[more]

PMID: 26139989

Similar Datasets

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

Project description: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.

| S-EPMC6111463 | biostudies-literature

Safety and Efficacy of Elobixibat, an Ileal Bile Acid Transporter Inhibitor, in Elderly Patients With Chronic Idiopathic Constipation According to Administration Time: Interim Analysis of Post-marketing Surveillance.

Project description:Background/aimsElobixibat, an ileal bile acid transporter (apical sodium-dependent bile acid transporter) inhibitor, was recently launched in Japan for the treatment of chronic idiopathic constipation. We conducted an interim analysis of post-marketing surveillance to evaluate the safety and efficacy of elobixibat in elderly patients with chronic constipation and compared the efficacy according to administration time.MethodsSafety and efficacy outcomes were evaluated through patient interviews for 4 weeks.ResultsAdverse drug reactions (ADRs) were observed in 5.24% of the 1049 patients analyzed; diarrhea (2.19%) and abdominal pain (1.81%) were the most common. A serious ADR of death was reported in one patient (0.10%). The incidence of ADRs in the ≥ 65-year old or ≥ 75-year-old subpopulation was similar to that in the total patient population. Mean bowel movements per week significantly increased from 2.9 ± 2.5 at baseline to 5.0 ± 3.1 (P < 0.001) at Week 2 and 5.3 ± 2.6 (P < 0.001) at Week 4. The mean Bristol Stool Form Scale score significantly increased from 2.3 ± 1.4 at baseline to 3.8 ± 1.3 (P < 0.001) at Week 2 and 3.9 ± 1.1 at Week 4 (P < 0.001). Bowel movements significantly increased in the elderly population and subpopulations receiving elobixibat before breakfast, lunch, or dinner. The median time to bowel movement was 5 hours.ConclusionThe results suggested that elobixibat was well-tolerated and efficacious in elderly patients with chronic constipation and can be administered before any meals.

| S-EPMC9274463 | biostudies-literature

A randomized placebo-controlled phase IIb trial of a3309, a bile acid transporter inhibitor, for chronic idiopathic constipation.

Project description:ObjectivesA3309 is a minimally absorbed ileal bile acid (BA) transporter (IBAT) inhibitor. We conducted an 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, phase IIb study, which evaluated A3309 in patients with chronic idiopathic constipation (CIC).MethodsPatients with CIC (modified Rome III criteria and <3 complete (CSBM) spontaneous bowel movements (SBMs)/week during the 2-week baseline) were randomized to 5, 10, or 15 mg A3309 or placebo once daily. The primary end point was change in SBM number during week 1 compared with baseline. Other bowel and abdominal symptoms were assessed as secondary end points. Serum 7αC4 and lipids were evaluated as biomarkers of BA synthesis/loss.ResultsIn all, 190 patients (mean 48 years, 90% female) were randomized. Mean increase (95% confidence interval) in SBM for week 1 were 1.7 (0.7-2.8) for placebo vs. 2.5 (1.5-3.5), 4.0 (2.9-5.0), and 5.4 (4.4-6.4) for 5 mg, 10 mg (P<0.002), and 15 mg (P<0.001) A3309, respectively. Increased stool frequency was maintained over 8 weeks. Time to first SBM and CSBM were significantly reduced in the 10- and 15-mg A3309 groups compared with placebo. Straining and bloating decreased with A3309 compared with placebo (P<0.05). Increased 7αC4 and reduced low-density lipoprotein cholesterol with A3309 suggested increased BA synthesis and BA loss. The most common adverse events (AEs) were abdominal pain and diarrhea, which occurred most commonly in the 15-mg A3309 group. No drug-related serious AEs were observed.ConclusionsA3309 increased stool frequency and improved constipation-related symptoms in CIC; effects were maintained over 8 weeks of treatment.

| S-EPMC3188811 | biostudies-literature

Effect of single and multiple doses of elobixibat, an ileal bile acid transporter inhibitor, on chronic constipation: A randomized controlled trial.

Project description:AimsElobixibat is a minimally absorbed ileal bile acid transporter inhibitor. This study aimed to investigate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of elobixibat in Japanese patients with chronic constipation.MethodsThis study consisted of single-dose and multiple-dose tests with a dose-escalating design. Sixty patients including females and males were randomized into five dose levels of elobixibat (2.5, 5, 10, 15 or 20 mg, n = 10 per level) and corresponding placebo (n = 2 per group). A crossover design was used to examine food effect in single-dose test. Patients received test tablets once daily for 14 days in multiple-dose test. We assessed pharmacokinetic-dose proportionality, levels of serum high- and low-density lipoprotein cholesterol and plasma 7?-hydroxy-4-cholesten-3-one (C4), food effect and sex-specific effect. Adverse events and bowel functions such as bowel movements, stool consistency and straining were also evaluated.ResultsFood consumption reduced systemic exposure by around 80% [e.g. least squares mean (ratio of breakfast/no breakfast) maximum plasma concentration: 0.2085 (90% confidence interval, 0.1371-0.3172) at 15 mg] while increased plasma C4 level (P < 0.001). In the multiple-dose test, elobixibat reduced low-density lipoprotein cholesterol and increased C4 whilst unaltering high-density lipoprotein cholesterol level. The increased spontaneous bowel movement frequency was correlated with higher dosage and higher C4 level (R2 = 0.5929 at Week 2). Adverse events were mainly gastrointestinal symptoms, most of which were mild.ConclusionsElobixibat should be taken before breakfast. Once-daily administration of elobixibat was found to be safe and tolerated up to 20 mg in female and male patients with chronic constipation.

| S-EPMC6138487 | biostudies-literature

Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis.

Project description:Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) are rare, inherited cholestatic liver disorders that manifest in infants and children and are associated with impaired bile flow (ie cholestasis), pruritus and potentially fatal liver disease. There are no effective or approved pharmacologic treatments for these diseases (standard medical treatments are supportive only), and new, noninvasive options would be valuable. Typically, bile acids undergo biliary secretion and intestinal reabsorption (ie enterohepatic circulation). However, in these diseases, disrupted secretion of bile acids leads to their accumulation in the liver, which is thought to underlie pruritus and liver-damaging inflammation. One approach to reducing pathologic bile acid accumulation in the body is surgical biliary diversion, which interrupts the enterohepatic circulation (eg by diverting bile acids to an external stoma). These procedures can normalize serum bile acids, reduce pruritus and liver injury and improve quality of life. A novel, nonsurgical approach to interrupting the enterohepatic circulation is inhibition of the ileal bile acid transporter (IBAT), a key molecule in the enterohepatic circulation that reabsorbs bile acids from the intestine. IBAT inhibition has been shown to reduce serum bile acids and pruritus in trials of paediatric cholestatic liver diseases. This review explores the rationale of inhibition of the IBAT as a therapeutic target, describes IBAT inhibitors in development and summarizes the current data on interrupting the enterohepatic circulation as treatment for cholestatic liver diseases including ALGS and PFIC.

| S-EPMC7496162 | biostudies-literature

Ileal bile acid transporter inhibition in Cyp2c70 KO mice ameliorates cholestatic liver injury.

Project description:Cyp2c70 is the liver enzyme in rodents responsible for synthesis of the primary 6-hydroxylated muricholate bile acid (BA) species. Cyp2c70 KO mice are devoid of protective, hydrophilic muricholic acids, leading to a more human-like BA composition and subsequent cholestatic liver injury. Pharmacological inhibition of the ileal BA transporter (IBAT) has been shown to be therapeutic in cholestatic models. Here, we aimed to determine if IBAT inhibition with SC-435 is protective in Cyp2c70 KO mice. As compared to WT mice, we found male and female Cyp2c70 KO mice exhibited increased levels of serum liver injury markers, and our evaluation of liver histology revealed increased hepatic inflammation, macrophage infiltration, and biliary cell proliferation. We demonstrate serum and histologic markers of liver damage were markedly reduced with SC-435 treatment. Additionally, we show hepatic gene expression in pathways related to immune cell activation and inflammation were significantly upregulated in Cyp2c70 KO mice and reduced to levels indistinguishable from WT with IBAT inhibition. In Cyp2c70 KO mice, the liver BA content was significantly increased, enriched in chenodeoxycholic acid, and more hydrophobic, exhibiting a hydrophobicity index value and red blood cell lysis properties similar to human liver BAs. Furthermore, we determined IBAT inhibition reduced the total hepatic BA levels but did not affect overall hydrophobicity of the liver BAs. These findings suggest that there may be a threshold in the liver for pathological accretion of hydrophobic BAs and reducing hepatic BA accumulation can be sufficient to alleviate liver injury, independent of BA pool hydrophobicity.

| S-EPMC9460185 | biostudies-literature

Organic Solute Transporter ?-? Protects Ileal Enterocytes From Bile Acid-Induced Injury.

Project description:Ileal bile acid absorption is mediated by uptake via the apical sodium-dependent bile acid transporter (ASBT), and export via the basolateral heteromeric organic solute transporter ?-? (OST?-OST?). In this study, we investigated the cytotoxic effects of enterocyte bile acid stasis in Ost?-/- mice, including the temporal relationship between intestinal injury and initiation of the enterohepatic circulation of bile acids.Ileal tissue morphometry, histology, markers of cell proliferation, gene, and protein expression were analyzed in male and female wild-type and Ost?-/- mice at postnatal days 5, 10, 15, 20, and 30. Ost?-/-Asbt-/- mice were generated and analyzed. Bile acid activation of intestinal Nrf2-activated pathways was investigated in Drosophila.As early as day 5, Ost?-/- mice showed significantly increased ileal weight per length, decreased villus height, and increased epithelial cell proliferation. This correlated with premature expression of the Asbt and induction of bile acid-activated farnesoid X receptor target genes in neonatal Ost?-/- mice. Expression of reduced nicotinamide adenine dinucleotide phosphate oxidase-1 and Nrf2-anti-oxidant responsive genes were increased significantly in neonatal Ost?-/- mice at these postnatal time points. Bile acids also activated Nrf2 in Drosophila enterocytes and enterocyte-specific knockdown of Nrf2 increased sensitivity of flies to bile acid-induced toxicity. Inactivation of the Asbt prevented the changes in ileal morphology and induction of anti-oxidant response genes in Ost?-/- mice.Early in postnatal development, loss of Ost? leads to bile acid accumulation, oxidative stress, and a restitution response in ileum. In addition to its essential role in maintaining bile acid homeostasis, Ost?-Ost? functions to protect the ileal epithelium against bile acid-induced injury. NCBI Gene Expression Omnibus: GSE99579.

| S-EPMC6009794 | biostudies-literature

Linaclotide (Linzess) for Irritable Bowel syndrome With Constipation and For Chronic Idiopathic Constipation.

Project description:Linaclotide (Linzess) for irritable bowel syndrome with constipation and for chronic idiopathic constipation.

| S-EPMC3638410 | biostudies-literature

Elobixibat and its potential role in chronic idiopathic constipation.

Project description: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.

| S-EPMC4107709 | biostudies-literature

The Cost Effectiveness of Lubiprostone in Chronic Idiopathic Constipation.

Project description:OBJECTIVE:The objective of this study was to evaluate the cost effectiveness of lubiprostone, prucalopride, placebo and immediate referral to secondary care in chronic idiopathic constipation (CIC) in an economic model that was used by the UK National Institute for Health and Care Excellence (NICE) in developing guidance. METHODS:We developed a cohort state-transition model to reflect the treatment pathway in CIC from the UK NHS and personal social services perspective. Time on treatment was determined by a treatment continuation rule using data from an indirect comparison and survival curves fitted to long-term data. Quality of life was defined by whether CIC was resolved or unresolved, using published values. Costs were determined by drug acquisition costs, invasive procedures and healthcare resource use (associated with resolved or unresolved CIC), using published UK sources. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS:Over a 10-year time horizon, lubiprostone was more costly and more effective than placebo and immediate referral to secondary care, with incremental cost-effectiveness ratios (ICERs) of £58,979 and £21,152. Lubiprostone dominated prucalopride in the base case and with a time horizon of 1 year. The main sensitivity for the comparison against placebo was the assumptions around placebo cost and efficacy. The main sensitivity for the comparison against prucalopride was the endpoint used in the indirect comparison. CONCLUSION:Lubiprostone may be cost effective compared with prucalopride or immediate referral but not compared with placebo in the base case. The implementation of the guidance issued by NICE should increase quality of life for patients with CIC and provide a further treatment option.

| S-EPMC6103927 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data