Bile Acid Transporter Inhibitor Research Articles

Efficacy of elobixibat as bowel preparation agent for colonoscopy: Prospective, randomized, multi‐center study

Background and AimElobixibat is a novel ileal bile acid transporter inhibitor. This study aimed to compare the efficacy, tolerability, and safety of the combination of elobixibat and 1 L of polyethylene glycol formulation containing ascorbic acid (PEG‐Asc) solution versus the combination of sodium picosulfate and 1‐L PEG‐Asc solution as bowel preparation for colonoscopy.MethodsThis multi‐center, randomized, observer‐blinded, non‐inferiority study recruited 210 outpatients who were assigned to either the elobixibat plus 1‐L PEG‐Asc group (group A) or the sodium picosulfate plus 1‐L PEG‐Asc group (group B). The quality of the bowel cleansing level was assessed by the Boston Bowel Preparation Scale (BBPS) and compared the bowel cleansing level between the groups. Data regarding bowel preparation time, patients’ tolerability, and adverse events were also analyzed.ResultsData for 196 patients (99 in group A and 97 in group B) were analyzed finally. BBPS was comparable between group A and B (8.3 ± 0.9 vs. 8.3 ± 0.7; P = 0.88). Consequently, the adequate bowel preparation rate in groups A and B was 95.0% and 99.0%, respectively (−4.0%, 95% CI −9.3 to 1.5). Bowel preparation time in group A was similar to that in group B (348.2 ± 79.8 min vs. 330.8 ± 82.5 min; P = 0.13), whereas, sleep disturbance was significantly less frequent in group A than in group B (10.2% vs. 22.7%; P = 0.02).ConclusionsThe combination of elobixibat and 1‐L PEG‐Asc can be considered an alternative bowel preparation for colonoscopy considering the equivalent bowel cleansing effect and less frequent sleep disturbance. The Japan Registry of Clinical Trials (jRCTs41180026).

Gut-restricted apical sodium-dependent bile acid transporter inhibitor attenuates alcohol-induced liver steatosis and injury in mice.

Recent studies have shown that human and experimental alcohol-related liver disease (ALD) is robustly associated with dysregulation of bile acid homeostasis, which may in turn modulate disease severity. Pharmacological agents targeting bile acid metabolism and signaling may be potential therapeutics for ALD. The potential beneficial effects of a gut-restricted apical sodium-dependent bile acid transporter (ASBT) inhibitor were studied in a chronic-plus-binge ALD mouse model. Blocking intestinal bile acid reabsorption by the gut-restricted ASBT inhibitor GSK2330672 attenuated hepatic steatosis and liver injury in a chronic-plus-binge ALD mouse model. Alcohol feeding is associated with intestinal bile acid accumulation but paradoxically impaired ileal farnesoid×receptor (FXR) function, and repressed hepatic cholesterol 7α-hydrolase (CYP7A1) expression despite decreased hepatic small heterodimer partner (SHP) and ileal fibroblast growth factor 15 (FGF15) expression. ASBT inhibitor treatment decreased intestinal bile acid accumulation and increased hepatic CYP7A1 expression, but further decreased ileal FXR activity. Alcohol feeding induces serum bile acid concentration that strongly correlates with a liver injury marker. However, alcohol-induced serum bile acid elevation is not due to intrahepatic bile acid accumulation but is strongly and positively associated with hepatic multidrug resistance-associated protein 3 (MRP4) and MRP4 induction but poorly associated with sodium-taurocholate cotransporting peptide (NTCP) expression. ASBT inhibitor treatment decreases serum bile acid concentration without affecting hepatocyte basolateral bile acid uptake and efflux transporters. ASBT inhibitor treatment corrects alcohol-induced bile acid dysregulation and attenuates liver injury in experimental ALD.

Pyrrolizidine Alkaloids Disturb Bile Acid Homeostasis in the Human Hepatoma Cell Line HepaRG.

1,2-unsaturated pyrrolizidine alkaloids (PAs) belong to a group of secondary plant metabolites. Exposure to PA-contaminated feed and food may cause severe hepatotoxicity. A pathway possibly involved in PA toxicity is the disturbance of bile acid homeostasis. Therefore, in this study, the influence of four structurally different PAs on bile acid homeostasis was investigated after single (24 h) and repeated (14 days) exposure using the human hepatoma cell line HepaRG. PAs induce a downregulation of gene expression of various hepatobiliary transporters, enzymes involved in bile acid synthesis, and conjugation, as well as several transcription regulators in HepaRG cells. This repression may lead to a progressive impairment of bile acid homeostasis, having the potential to accumulate toxic bile acids. However, a significant intracellular and extracellular decrease in bile acids was determined, pointing to an overall inhibition of bile acid synthesis and transport. In summary, our data clearly show that PAs structure-dependently impair bile acid homeostasis and secretion by inhibiting the expression of relevant genes involved in bile acid homeostasis. Furthermore, important biliary efflux mechanisms seem to be disturbed due to PA exposure. These mole-cular mechanisms may play an important role in the development of severe liver damage in PA-intoxicated humans.

Elobixibat, an ileal bile acid transporter inhibitor, ameliorates non-alcoholic steatohepatitis in mice.

Recent studies have suggested that several types of toxic bile acids (BAs) are involved in the pathogenesis of non-alcoholic steatohepatitis (NASH). In the present study, we aimed to determine whether elobixibat, an ileal bile acid transporter (IBAT) inhibitor, would ameliorate NASH in mice. C57BL/6N mice were fed a methionine and choline-deficient (MCD) to induce NASH or standard diet as control for 8weeks (n = 5 per group). The MCD diet-fed mice were administered elobixibat 5days a week for 4weeks by gavage (n = 5). The effects of the treatments on liver histopathology, proinflammatory cytokine concentrations, intestinal epithelial tight junctions, and the intestinal microbial composition were then assessed. In MCD-fed mice, hepatic fibrosis and inflammatory cell infiltration developed, and the serum aspartate transaminase activity and BA concentration were higher than the control. In addition, the proinflammatory cytokine concentrations were high in the liver and mesenteric lymph nodes (MLN), and the expression of intestinal epithelium tight junction proteins, claudin1, was increased. In the intestinal microbial composition, the abundance of the Lachnospiraceae and Ruminococcaeae were decreased, whereas that of the Enterobacteriaceae was increased. Treatment with elobixibat reduced the serum BA and increased the fecal BA concentration, and ameliorated the liver inflammation and fibrosis. It also reduced the expression of proinflammatory cytokines in the liver and MLNs, and transforming growth factor-β expression in the liver. Finally, elobixibat normalized intestinal tight junction protein level and the composition of the intestinal microbiota. Elobixibat ameliorates NASH-related histopathology, reduces cytokine expression, and normalizes the intestinal microbial composition in MCD-fed mice, which suggests that it may represent a promising candidate for the therapy of NASH.

Review article: Elobixibat: a novel treatment for chronic constipation.

A subset of patients with chronic constipation has associated slow colonic transit and reduced faecal bile acid excretion. In addition to traditional approaches to treat chronic constipation, a novel therapeutic option is to increase the colonic concentration of intraluminal bile acids. This can be achieved through inhibition of the ileal bile acid transporter. To evaluate the evidence for efficacy and safety of an ileal bile acid transport inhibitor in the treatment of chronic constipation METHODS: We reviewed published literature on elobixibat, based on a PubMed search. Elobixibat is a novel ileal bile acid transport inhibitor that has demonstrated efficacy in proof of concept studies in experimental animals as well as phase 1, 2 and 3 trials in humans. Phase 4 studies have now documented that the beneficial effects are related to increase in the secretory bile acids in the colon as measured by stool bile acid content. The studies documented efficacy in patients with severe constipation, which is often associated with slow colonic transit. These changes in bile acid composition were associated with minor differences in the faecal microbiota in patients treated with elobixibat compared to placebo. Elobixibat appears to be safe. The only adverse effects of note are associated with its pharmacological actions in patients with chronic constipation,namely the induction of diarrhoea and abdominal pain. This new class of compound appears to be safe and efficacious in the treatment of chronic constipation.

Improvements in the Oral Absorption and Anticancer Efficacy of an Oxaliplatin-Loaded Solid Formulation: Pharmacokinetic Properties in Rats and Nonhuman Primates and the Effects of Oral Metronomic Dosing on Colorectal Cancer.

ObjectiveThe anticancer efficacy of orally administered chemotherapeutics is often constrained by low intestinal membrane permeability and oral bioavailability. In this context, we designed a solid oral formulation of oxaliplatin (OP), a third-generation cisplatin analog, to improve oral bioavailability and investigate its application in metronomic chemotherapy.MethodsAn ion-pairing complex of OP with a permeation enhancer, Nα-deoxycholyl-l-lysyl-methylester (DLM), was successfully prepared and then mixed with dispersing agents (including poloxamer 188 and Labrasol) to form the solid, amorphous oral formulation OP/DLM (OP/DLM-SF; hereafter, ODSF).ResultsThe optimized powder formulation was sized in the nanoscale range (133±1.47 nm). The effective permeability of OP increased by 12.4-fold after ionic complex formation with DLM and was further increased by 24.0-fold after incorporation into ODSF. ODSF exhibited respective increases of 128% and 1010% in apparent permeability across a Caco-2 monolayer, compared to OP/DLM and OP. Furthermore, inhibition of bile acid transporters by actinomycin D and caveola-mediated uptake by brefeldin in Caco-2 cell monolayers reduced the apparent permeability values of ODSF by 58.4% and 51.1%, respectively, suggesting predominant roles for bile acid transporters and caveola-mediated transport in intestinal absorption of ODSF. In addition, macropinocytosis and paracellular and transcellular passive transport significantly influenced the intestinal permeation of ODSF. The oral bioavailabilities of ODSF in rats and monkeys were 68.2% and 277% higher, respectively, than the oral bioavailability of free OP. In vivo analyses of anticancer efficacy in CT26 and HCT116 cell-bearing mice treated with ODSF demonstrated significant suppression of tumor growth, with respective maximal tumor volume reductions of 7.77-fold and 4.07-fold, compared to controls.ConclusionODSF exhibits therapeutic potential, constituting an effective delivery system that increases oral bioavailability, with applications to metronomic chemotherapy.

Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders.

Biliary atresia is a rare cholestatic liver disease that presents in infants and rapidly advances to death in the absence of intervention. As a result of blockage or destruction of the biliary tract, bile acids accumulate and drive inflammation, fibrosis, and disease progression. The standard of care, Kasai portoenterostomy (KPE), is typically performed shortly after diagnosis (currently at ~ 2months of age) and aims to restore bile flow and relieve cholestasis. Nevertheless, most patients continue to experience liver injury from accumulation of bile acids after KPE, since there are no known effective therapeutics that may enhance survival after KPE. Improving cholestasis via interruption of the enterohepatic circulation of bile acids may directly attenuate hepatic bile acid retention and reduce the risk of early organ failure. Directly addressing intrahepatic accretion of bile acids to avoid inherent bile acid toxicities provides an attractive and plausible therapeutic target for biliary atresia. This review explores the novel therapeutic concept of inhibiting the sole ileal bile acid transporter (IBAT), also known as ASBT (apical sodium-bile acid transporter, encoded by SLC10A2), as a means to reduce hepatic bile acid concentration after KPE. By reducing return of bile acids to the cholestatic liver, IBAT inhibitors may potentially lessen or delay liver damage associated with the hepatotoxicity and cholangiopathy of bile acid accumulation. The clinical programs of 2 IBAT inhibitors in development for the treatment of pediatric cholestatic liver diseases, maralixibat and odevixibat, are highlighted.

Emerging Therapeutic Options for Chronic Pruritus.

Chronic pruritus, defined as an unpleasant sensation resulting in a need to scratch that lasts more than 6 weeks, is a prevalent and bothersome symptom associated with both cutaneous and systemic conditions. Due to complex pathogenesis and profuse contributing factors, chronic pruritus therapy remains challenging. Regardless of the well-established antipruritic properties of classic pharmacotherapy (topical therapy, phototherapy and systemic therapy), these methods often provide insufficient relief for affected individuals. Owing to the growing interest in the field of pruritic research, further experimental and clinical data have emerged, continuously supporting the possibility of instigating novel therapeutic measures. This review covers the most relevant current modalities remaining under investigation that possess promising perspectives of approval in the near future, especially opioidergic drugs (mu-opioid antagonists and kappa-opioid agonists), neurokinin-1 receptor antagonists, biologic drugs, Janus kinase inhibitors, ileal bile acid transporter inhibitors, aryl hydrocarbon receptor agonists and histamine H4 receptor antagonists.

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

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.

Changes in the gut microbiota caused by ASBTi suppress intrahepatic steatosis and inflammation in a mouse model of non-alcoholic fatty liver disease (NAFLD)

Abstract Although the estimated prevalence of NAFLD is approximately 25%, an effective treatment has not been established. Recently, gut microbiota has been shown to affect the pathogenesis of NAFLD. In this study, the protective effect of Apical Sodium-dependent Bile acid Transporter inhibitor (ASBTi) against NAFLD was investigated in mice fed a high-fat diet for 12 weeks (HFD mice) via changing their gut microbiota. ASBTi mice were mice treated with ASBTi (2.5 μmol/kg/day) during HFD feeding. For fecal microbiota transplantation (FMT), stools were collected from HFD mice and ASBTi mice. Fecal materials obtained from HFD mice and ASBTi mice were transplanted to normal mice, fed HFD for 12 weeks, and designated as HFD-FMT mice and ASBTi-FMT mice, respectively. Microbiota in these groups of mice were analyzed by 16S rRNA gene sequencing. The degrees of hepatic steatosis and inflammation in these mice were determined pathologically. The shannon index of the microbiota from ASBTi mice (3.31±0.19) and ASBTi-FMT mice (3.29±0.18) was significantly high as compared to that from HFD mice (2.90±0.19) and HFD-FMT mice (2.89±0.16). Steatosis and inflammation in the liver of HFD mice and HFD-FMT mice were shown to be pathologically severe and NAFLD Activity Score (NAS) was 7.67±0.58 in HFD mice and 5.67±2.08 in HFD-FMT mice. However, those in the liver of ASBTi mice and ASBTi-FMT mice were improved and NAS was reduced in ASBTi mice (1.67±0.58) and in ASBTi-FMT mice (2.67±0.58). These results suggest that changes in the gut microbiota caused by ASBTi suppress intrahepatic steatosis and inflammation in NAFLD mice. Elobixibat can be expected to prevent fatty liver.

The Efficacy and Safety of Elobixibat for the Elderly with Chronic Constipation: A Multicenter Retrospective Cohort Study.

Materials and Methods This was a multicenter retrospective cohort study. The subjects were patients aged ≥20 years treated for chronic constipation from May 2018 to November 2019 at 12 related institutions. Patients were divided into ≤74 years and ≥75 years old. Elobixibat at 10 mg/day was prescribed for two weeks. We then analyzed the discontinuation due to ineffectiveness, change of spontaneous bowel movements (SBM), stool consistency, the time until the first SBM, adverse events, and effect-related factors. Results There were 140 cases (61 males) evaluated, with an average age of 72.1 ± 13.6 years (≤74 years: 71 cases; ≥75 years: 69 cases). The discontinuation rate was 7.9%. The SBM (times/week) increased from 2.86 to 6.08 (p < 0.001). The overall SBM improvement rate was 74.0% (≤74 years: 78.2% vs. ≥75 years: 68.9%, p = 0.31; male: 75.0% vs. female: 73.3%, p = 0.78). The overall improvement rate of stool consistency was 59.6% (≤74 years: 62.9%, ≥75 years: 56.1%, p = 0.42). The time until the first SBM (hours) for those ≤74 years and ≥75 years was 17.2 ± 14.3 and 11.2 ± 8.4 (p = 0.04). Adverse event rates for those ≤74 years and ≥75 years were 28.2% and 10.1% (p < 0.01). There were no significant effect-related factors for gender, age, and use of laxatives. Conclusions Short-period elobixibat is shown to be effective also for the elderly and male.

Attenuation of the Hepatoprotective Effects of Ileal Apical Sodium Dependent Bile Acid Transporter (ASBT) Inhibition in Choline-Deficient L-Amino Acid-Defined (CDAA) Diet-Fed Mice.

Non-alcoholic fatty liver disease (NAFLD) is a major growing worldwide health problem. We previously reported that interruption of the enterohepatic circulation of bile acids using a non-absorbable apical sodium-dependent bile acid transporter inhibitor (ASBTi; SC-435) reduced the development of NAFLD in high fat diet fed mice. However, the ability of ASBTi treatment to impact the progression of NAFLD to non-alcoholic steatohepatitis (NASH) and fibrosis in a diet-induced mouse model remains untested. In the current study, we assessed whether ASBTi treatment is hepatoprotective in the choline-deficient, L-amino acid-defined (CDAA) diet model of NASH-induced fibrosis.Methods: Male C57Bl/6 mice were fed with: (A) choline-sufficient L-amino acid-defined diet (CSAA) (31 kcal% fat), (B) CSAA diet plus ASBTi (SC-435; 60 ppm), (C) CDAA diet, or (D) CDAA diet plus ASBTi. Body weight and food intake were monitored. After 22 weeks on diet, liver histology, cholesterol and triglyceride levels, and gene expression were measured. Fecal bile acid and fat excretion were measured, and intestinal fat absorption was determined using the sucrose polybehenate method.Results: ASBTi treatment reduced bodyweight gain in mice fed either the CSAA or CDAA diet, and prevented the increase in liver to body weight ratio observed in CDAA-fed mice. ASBTi significantly reduced hepatic total cholesterol levels in both CSAA and CDAA-fed mice. ASBTi-associated significant reductions in hepatic triglyceride levels and histological scoring for NAFLD activity were observed in CSAA but not CDAA-fed mice. These changes correlated with measurements of intestinal fat absorption, which was significantly reduced in ASBTi-treated mice fed the CSAA (85 vs. 94%, P < 0.001) but not CDAA diet (93 vs. 93%). As scored by Ishak staging of Sirius red stained liver sections, no hepatic fibrosis was evident in the CSAA diet mice. The CDAA diet-fed mice developed hepatic fibrosis, which was increased by the ASBTi.Conclusions: ASBT inhibition reduced intestinal fat absorption, bodyweight gain and hepatic steatosis in CSAA diet-fed mice. The effects of the ASBTi on steatosis and fat absorption were attenuated in the context of dietary choline-deficiency. Inhibition of intestinal absorption of fatty acids may be involved in the therapeutic effects of ASBTi treatment.

Maralixibat Treatment Significantly Reduces Pruritus and Serum Bile Acids in Patients with Alagille Syndrome: Results from a Randomized Phase II Study with 4 Years of Follow-Up

Background: Alagille syndrome (ALGS) is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical sodium-dependent bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in ALGS. Methods: ICONIC was a randomized, placebo-controlled, drug-withdrawal, Phase IIb study with open-label extension in children with ALGS (NCT02160782). Eligible participants had >3x normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 μg/kg once daily, participants were randomized 1:1 to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat to Week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 μg/kg twice daily. The primary endpoint was the mean sBA change during the randomized withdrawal in participants with ≥50% sBA reduction by Week 18. Cholestasis was assessed using pruritus (observer-, patient- and clinician-rated; 0-4 scale), growth and liver function. Findings: Between October 2014 and August 2015, 31 participants (mean age: 5.4 years) were enrolled and 28 analyzed at Week 48. In the randomized-withdrawal period, participants switched to placebo experienced significant increases in sBA (+94 µmol/L; p=0.0130) and pruritus (+1.7 pts; p<0.0001), whereas those continuing maralixibat maintained treatment response. From Baseline to Week 48, sBA (‑96 µmol/L; p=0.0058), pruritus (-1.6 pts, p<0.0001), xanthomas (-0.9 pts; p=0.0006), height (+0.18 z-score; p=0.0704) and quality of life (+9 pts; p=0.0200) improved. In those continuing to Week 204 (n=15) all improvements were maintained. Throughout, no increase in adverse event frequency or severity was observed. Interpretation: In children with ALGS, maralixibat is the first agent to demonstrate significant, durable, and clinically meaningful improvements in cholestasis. Maralixibat represents a new treatment paradigm for chronic cholestasis in ALGS. Trial Registration: NCT02160782 Funding: Funded by Mirum Pharmaceuticals. Declaration of Interests: EG has received consultancy fees from Mirum Pharmaceuticals, Albireo, and Laboratoires CTRS. AB has received grants and research support from Mirum Pharmaceuticals. ES has received consultancy fees from Mirum Pharmaceuticals and Albireo and has received travel support from Albireo. KDRS has received consultancy fees from Retrophin and Sanitarium Health and Wellbeing Company and is a stockholder in Asklepion Pharmaceuticals, LLC, Ausio Pharmaceuticals, LLC, and Aliveris s.r.l. CK and TJ are shareholders in Mirum Pharmaceuticals. NKD is a stockholder in and employee of Takeda. PV and AJW are stockholders in and employees of Mirum Pharmaceuticals. EJ has received consultancy fees from Laboratoires CTRS and is a stockholder of Laboratoires CTRS and Vivet Therapeutics AD was an employee of Lumina Pharmaceuticals and has received personal fees from Shire Pharmaceuticals. WH, MS, LH, AL, FL, AL, and JS have no conflicts of interest to declare. Ethics Approval Statement: This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines and approved by institutional review boards and ethics committees. Informed consent (and assent) was obtained from the participant or their legal guardian.

Primary biliary cholangitis: pathogenesis and therapeutic opportunities.

Primary biliary cholangitis is a chronic, seropositive and female-predominant inflammatory and cholestatic liver disease, which has a variable rate of progression towards biliary cirrhosis. Substantial progress has been made in patient risk stratification with the goal of personalized care, including early adoption of next-generation therapy with licensed use of obeticholic acid or off-label fibrate derivatives for those with insufficient benefit from ursodeoxycholic acid, the current first-line drug. The disease biology spans genetic risk, epigenetic changes, dysregulated mucosal immunity and altered biliary epithelial cell function, all of which interact and arise in the context of ill-defined environmental triggers. A current focus of research on nuclear receptor pathway modulation that specifically and potently improves biliary excretion, reduces inflammation and attenuates fibrosis is redefining therapy. Patients are benefiting from pharmacological agonists of farnesoid X receptor and peroxisome proliferator-activated receptors. Immunotherapy remains a challenge, with a lack of target definition, pleiotropic immune pathways and an interplay between hepatic immune responses and cholestasis, wherein bile acid-induced inflammation and fibrosis are dominant clinically. The management of patient symptoms, particularly pruritus, is a notable goal reflected in the development of rational therapy with apical sodium-dependent bile acid transporter inhibitors.

High-Throughput Screening to Evaluate Inhibition of Bile Acid Transporters Using Human Hepatocytes Isolated From Chimeric Mice.

Cholestasis resulting from hepatic bile acid efflux transporter inhibition may contribute to drug-induced liver injury (DILI). This condition is a common safety-related reason for drug attrition and withdrawal. To screen for safety risks associated with efflux transport inhibition, we developed a high-throughput cellular assay for different drug discovery phases. Hepatocytes isolated from chimeric mice with humanized livers presented gene expression resembling that of the human liver and demonstrated apical membrane polarity when sandwiched between Matrigel and collagen. The fluorescent bile acid-derivative cholyl-l-lysyl-fluorescein (CLF) was used to quantify drug-induced efflux transport inhibition in hepatocytes. Cyclosporine inhibited CLF accumulation in the apical bile canalicular lumen in a concentration-dependent manner. The assay had equivalent predictive power to a primary human hepatocyte-based assay and greater predictive power than an assay performed with rat hepatocytes. Predictive power was tested using 45 pharmaceutical compounds, and 91.3% of the compounds with cholestatic potential (21/23) had margins (IC50/Cmax)<20. In contrast, 90.9% (20/22) of compounds without cholestatic potential had IC50/Cmax>20. Assay sensitivity and specificity were 91.3% and 90.9%, respectively. We suggest that this improved assay performance could result from higher expression of efflux transporters, metabolic pathways, and/or species differences. Given the long-term supply of cells from the same donor, the humanized mouse-derived hepatocyte-based CLF efflux assay could be a valuable tool for predicting cholestatic DILI.

What's in the pipeline for lower functional gastrointestinal disorders in the next 5 years?

The overall objectives of this review are to summarize actionable biomarkers for organic etiology of lower functional gastrointestinal disorders (FGIDs) that lead to individualized treatment for their FGIDs and to assess the pipeline for novel approaches to the management of constipation, diarrhea, and chronic abdominal pain in lower FGIDs. The new approaches to therapy include ion exchangers/transporters for functional constipation (sodium-glucose cotransporter 1, Na+/H+ exchanger 3, and solute carrier family 26 member 3 inhibitors), bile acid modulators for constipation such as ileal bile acid transporter inhibitors and fibroblast growth factor 19 analog for functional constipation, and bile acid sequestrants or farnesoid X receptor agonists for functional diarrhea. Treatment for chronic abdominal pain remains an unmet need in patients with lower FGIDs, and promising novel approaches include delayed-release linaclotide, nonclassical opioid visceral analgesics, and selective cannabinoid receptor agonists. The role of probiotics, fecal microbial transplantation, and possible future microbiome therapies is discussed.

&lt;p&gt;Intestinal transport mechanism and in vivo anticancer efficacy of a solid oral formulation incorporating an ion-pairing complex of pemetrexed with deoxycholic acid derivative&lt;/p&gt;

ObjectiveThe rational combination of immunotherapy with standard chemotherapy shows synergistic clinical activities in cancer treatment. In the present study, an oral powder formulation of pemetrexed (PMX) was developed to enhance intestinal membrane permeability and investigate its application in metronomic chemotherapy in combination with immunotherapy.MethodsPMX was ionically complexed with a bile acid derivative (Nα-deoxycholyl-l-lysyl-methylester; DCK) as a permeation enhancer and mixed with dispersing agents, such as poloxamer 188 (P188) and Labrasol, to form an amorphous oral powder formulation of PMX/DCK (PMX/DCK-OP).ResultsThe apparent permeability (Papp) of PMX/DCK-OP across a Caco-2 cell monolayer was 2.46- and 8.26-fold greater than that of PMX/DCK and free PMX, respectively, which may have been due to the specific interaction of DCK with bile acid transporters, as well as the alteration of membrane fluidity due to Labrasol and P188. Furthermore, inhibition of bile acid transporters by actinomycin D in Caco-2 cell monolayers decreased the Papp of PMX/DCK-OP by 75.4%, suggesting a predominant role of bile acid transporters in the intestinal absorption of PMX/DCK-OP. In addition, caveola/lipid raft-dependent endocytosis, macropinocytosis, passive diffusion, and paracellular transport mechanisms significantly influenced the permeation of PMX/DCK-OP through the intestinal membrane. Therefore, the oral bioavailability of PMX/DCK-OP in rats was 19.8%±6.93%, which was 294% higher than that of oral PMX. Moreover, an in vivo anticancer efficacy study in B16F10 cell-bearing mice treated with a combination of oral PMX/DCK-OP and intraperitoneal anti-PD1 exhibited significant suppression of tumor growth, and the tumor volume was maximally inhibited by 2.03- and 3.16-fold compared to the oral PMX/DCK-OP and control groups, respectively.ConclusionThese findings indicated the therapeutic potential of a combination of low-dose oral chemotherapy and immunotherapy for synergistic anticancer efficacy.

Treatment of Pruritus Secondary to Liver Disease.

Pruritus is a common extrahepatic symptom in various liver disorders, in particularly those with cholestatic features. This review summarizes epidemiology, pathophysiology, evidence-based therapeutic recommendations and currently investigated drugs for pruritus in hepatobiliary disorders. Recent epidemiological data suggest pruritus as a common and relevant symptom in immune-mediated liver diseases, i.e., primary biliary cholangitis (PBC) with over 70% affected patients, up to 56% suffering from chronic pruritus. The better pathophysiological understanding of hepatic pruritus has led to the identification of novel therapeutic targets, addressed in drug trials using KOR agonists, PPAR agonists, and ileal bile acid transporter inhibitors. Hepatic itch remains among the most agonizing symptoms for affected patients and a clinical challenge for physicians. Therapeutic recommendations include a guideline-based stepwise approach starting with cholestyramine, followed by rifampicin, naltrexone, and sertraline. Bezafibrate and ileal bile acid transporter inhibitors represent promising future anti-pruritic treatment options.

PS-193-Phase 2 open-label study with a placebo-controlled drug withdrawal period of the apical sodium-dependent bile acid transporter inhibitor maralixibat in children with Alagille Syndrome: 48-week interim efficacy analysis

PS-193-Phase 2 open-label study with a placebo-controlled drug withdrawal period of the apical sodium-dependent bile acid transporter inhibitor maralixibat in children with Alagille Syndrome: 48-week interim efficacy analysis

LBP-24-Safety, tolerability and efficacy of volixibat, an apical sodium-dependent bile acid transporter inhibitor, in adults with nonalcoholic steatohepatitis: 24-week interim analysis results from a phase 2 study

LBP-24-Safety, tolerability and efficacy of volixibat, an apical sodium-dependent bile acid transporter inhibitor, in adults with nonalcoholic steatohepatitis: 24-week interim analysis results from a phase 2 study