ArticlePloS one2014
Evaluation of the endothelin receptor antagonists ambrisentan, bosentan, macitentan, and sitaxsentan as hepatobiliary transporter inhibitors and substrates in sandwich-cultured human hepatocytes.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 2 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
29 citing papers in PubMed, 2 syntheses or guidelines pooled it, 76 citations in OpenAlex.
- Investigating Intestinal Transporter Involvement in Rivaroxaban Disposition through Examination of Changes in Absorption.Pharmaceutical research · 2021Pooled it
- Clinical Adverse Effects of Endothelin Receptor Antagonists: Insights From the Meta-Analysis of 4894 Patients From 24 Randomized Double-Blind Placebo-Controlled Clinical Trials.Journal of the American Heart Association · 2016Pooled it
- Disproportionality analysis of adverse events associated with endothelin receptor antagonists based on the FDA adverse event reporting system (FAERS).Frontiers in cardiovascular medicine · 2026Article
- Macitentan in the Treatment of Digital Ulcers in Patients with Systemic Rheumatic Autoimmune Diseases: A National Multicenter Study of 42 Patients.Journal of clinical medicine · 2025Article
- Predicting Systemic and Liver Bosentan Exposure Using Physiologically-Based Pharmacokinetic Modeling.CPT: pharmacometrics & systems pharmacology · 2025Article
- Endothelin receptor antagonists in chronic kidney disease.Nature reviews. Nephrology · 2025Review
- In Vitro-In Silico Models to Elucidate Mechanisms of Bile Acid Disposition and Cellular Aerobics in Human Hepatocytes.The AAPS journal · 2025Article
- Drug Interactions of Imperatorin and Curcumin on Macitentan in vitro and in vivo.Drug design, development and therapy · 2025Article
- Adverse Outcome Pathways Mechanistically Describing Hepatotoxicity.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Liver injury associated with endothelin receptor antagonists: a pharmacovigilance study based on FDA adverse event reporting system data.International journal of clinical pharmacy · 2024Article
- Targeting the Endothelin A Receptor in IgA Nephropathy.Kidney international reports · 2023Review
- Cost-utility analysis of Macitentan Vs. Bosentan in pulmonary atrial hypertension.Journal of family medicine and primary care · 2020Article
- Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury.Archives of toxicology · 2020Article
- Article
- A network meta-analysis for safety of endothelin receptor antagonists in pulmonary arterial hypertension.Cardiovascular diagnosis and therapy · 2019Article
- Evaluation of Drug Biliary Excretion Using Sandwich-Cultured Human Hepatocytes.European journal of drug metabolism and pharmacokinetics · 2019Review
- Can Bile Salt Export Pump Inhibition Testing in Drug Discovery and Development Reduce Liver Injury Risk? An International Transporter Consortium Perspective.Clinical pharmacology and therapeutics · 2018Review
- Transporters in Drug Development: 2018 ITC Recommendations for Transporters of Emerging Clinical Importance.Clinical pharmacology and therapeutics · 2018Review
- Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures.Archives of toxicology · 2018Article
- Prediction of Hepatic Efflux Transporter-Mediated Drug Interactions: When Is it Optimal to Measure Intracellular Unbound Fraction of Inhibitors?Journal of pharmaceutical sciences · 2017Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundInhibition of the transporter-mediated hepatobiliary elimination of bile salts is a putative mechanism for liver toxicity observed with some endothelin receptor antagonists (ERAs).
methodsSandwich-cultured human hepatocytes were used to study the hepatobiliary distribution and accumulation of exogenous taurocholate, ERAs and endogenous bile acids. The molecular mechanisms for findings in hepatocytes or clinical observations were further explored using either vesicular assays (efflux transporters) or transfected cell-lines (uptake transporters). Inhibition constants (IC50) were measured for the human hepatobiliary transporters bile salt export pump (BSEP), sodium taurocholate cotransporting polypeptide (NTCP), multidrug resistance protein 2 (MRP2), P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3.
resultsThe ERAs showed dose-dependent reductions in exogenous taurocholate cellular accumulation in human hepatocytes, with macitentan having the greatest effect. Consistent with their effects on bile acids, the ERAs inhibited bile transporters. IC50 values for OATP1B1 and OATP1B3 ranged from 2 µM for macitentan to 47 µM for ambrisentan. Macitentan and bosentan also inhibited NTCP with IC50 values of 10 and 36 µM, respectively. Similar to previously reported findings with sitaxsentan, BSEP inhibition was observed for bosentan and macitentan with IC50 values of 42 and 12 µM, respectively. In contrast, ambrisentan showed little or no inhibition of these transporters. Other transporters tested were weakly inhibited by the ERAs. Accumulation in hepatocytes was also a factor in the effects on bile transport. Macitentan demonstrated the greatest accumulation in human hepatocytes (∼100x) followed by sitaxsentan (∼40x), bosentan (∼20x) and ambrisentan (∼2x).
conclusionsSignificant differences in the inhibition of hepatic transporters were observed between the evaluated ERAs in vitro. Macitentan had the highest level of cellular accumulation and caused the greatest effects on bile acid distribution in human hepatocytes followed by sitaxsentan and bosentan. Ambrisentan showed a low potential to affect bile acids.
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