ArticleToxicological sciences : an official journal of the Society of Toxicology2016
Inhibition of Human Hepatic Bile Acid Transporters by Tolvaptan and Metabolites: Contributing Factors to Drug-Induced Liver Injury?
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 50 citations in OpenAlex.
- Regulatory guidelines do not accurately predict tolvaptan and metabolite interactions at BCRP, OATP1B1, and OAT3 transporters.Clinical and translational science · 2021Trial
- Vaptans: A Narrative Review of Pharmacokinetics, Pharmacogenetics, and Clinical Applications.Cells · 2026Review
- Identification of key immune genes of drug-induced liver injury induced by tolvaptan based on bioinformatics.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Potential amelioration of liver function by low-dose tolvaptan in heart failure patients.Toxicology reports · 2025Article
- Pharmacotherapy in kidney disease: what it takes to move from general guidance to specific recommendations to stratified subgroups of patients - the tale of autosomal dominant polycystic kidney disease (ADPKD).Expert opinion on drug metabolism & toxicology · 2025Review
- Altered bile acid and coproporphyrin-I disposition in patients with autosomal dominant polycystic kidney disease.British journal of clinical pharmacology · 2025Observational
- Tolvaptan safety in autosomal-dominant polycystic kidney disease; a focus on idiosyncratic drug-induced liver injury liabilities.Toxicological sciences : an official journal of the Society of Toxicology · 2025Review
- Evaluation of tolvaptan-associated hepatic disorder using different national pharmacovigilance databases.Scientific reports · 2024Article
- Ganoderma lucidum polysaccharide ameliorates cholesterol gallstone formation by modulating cholesterol and bile acid metabolism in an FXR-dependent manner.Chinese medicine · 2024Article
- Safety assessment of tolvaptan: real-world adverse event analysis using the FAERS database.Frontiers in pharmacology · 2024Article
- Hepatic Bile Acid Transporters and Drug-induced Hepatotoxicity.Toxicologic pathology · 2023Review
- Natural Peptide Toxins as an Option for Renewed Treatment of Type 2 Vasopressin Receptor-Related Diseases.Biology · 2023Review
- Stereoselective interaction of tolvaptan with amiodarone under racemic metabolic impact by CYP3A5 genotypes in heart failure patients.European journal of clinical pharmacology · 2022Article
- Quantitative Systems Toxicology Modeling Predicts that Reduced Biliary Efflux Contributes to Tolvaptan Hepatotoxicity.Clinical pharmacology and therapeutics · 2021Article
- Safety Profile of Tolvaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease.Therapeutics and clinical risk management · 2021Review
- A snake toxin as a theranostic agent for the type 2 vasopressin receptor.Theranostics · 2020Article
- The management of polycystic liver disease by tolvaptan.Clinical and molecular hepatology · 2020Article
- Altered Expression and Function of Hepatic Transporters in a Rodent Model of Polycystic Kidney Disease.Drug metabolism and disposition: the biological fate of chemicals · 2019Article
- Effect of a Common Genetic Variant (p.V444A) in the Bile Salt Export Pump on the Inhibition of Bile Acid Transport by Cholestatic Medications.Molecular pharmaceutics · 2019Article
- Altered Hepatobiliary Disposition of Tolvaptan and Selected Tolvaptan Metabolites in a Rodent Model of Polycystic Kidney Disease.Drug metabolism and disposition: the biological fate of chemicals · 2019Article
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
Abstract
Tolvaptan is a vasopressin V(2)-receptor antagonist that has shown promise in treating Autosomal Dominant Polycystic Kidney Disease (ADPKD). Tolvaptan was, however, associated with liver injury in some ADPKD patients. Inhibition of bile acid transporters may be contributing factors to drug-induced liver injury. In this study, the ability of tolvaptan and two metabolites, DM-4103 and DM-4107, to inhibit human hepatic transporters (NTCP, BSEP, MRP2, MRP3, and MRP4) and bile acid transport in sandwich-cultured human hepatocytes (SCHH) was explored. IC(50) values were determined for tolvaptan, DM-4103 and DM-4107 inhibition of NTCP (∼41.5, 16.3, and 95.6 μM, respectively), BSEP (31.6, 4.15, and 119 μM, respectively), MRP2 (>50, ∼51.0, and >200 μM, respectively), MRP3 (>50, ∼44.6, and 61.2 μM, respectively), and MRP4 (>50, 4.26, and 37.9 μM, respectively). At the therapeutic dose of tolvaptan (90 mg), DM-4103 exhibited a C(max)/IC(50) value >0.1 for NTCP, BSEP, MRP2, MRP3, and MRP4. Tolvaptan accumulation in SCHH was extensive and not sodium-dependent; intracellular concentrations were ∼500 μM after a 10-min incubation duration with tolvaptan (15 μM). The biliary clearance of taurocholic acid (TCA) decreased by 43% when SCHH were co-incubated with tolvaptan (15 μM) and TCA (2.5 μM). When tolvaptan (15 μM) was co-incubated with 2.5 μM of chenodeoxycholic acid, taurochenodeoxycholic acid, or glycochenodeoxycholic acid in separate studies, the cellular accumulation of these bile acids increased by 1.30-, 1.68-, and 2.16-fold, respectively. Based on these data, inhibition of hepatic bile acid transport may be one of the biological mechanisms underlying tolvaptan-associated liver injury in patients with ADPKD.
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