ArticleThe Journal of pharmacology and experimental therapeutics2015
Species differences in hepatobiliary disposition of taurocholic acid in human and rat sandwich-cultured hepatocytes: implications for drug-induced liver injury.
Article in The Journal of pharmacology and experimental therapeutics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 53 citations in OpenAlex.
- Inhibition of canalicular and sinusoidal taurocholate efflux by cholestatic drugs in human hepatoma HepaRG cells.Biopharmaceutics & drug disposition · 2022Article
- Comparative Study on Nanotoxicity in Human Primary and Cancer Cells.Nanomaterials (Basel, Switzerland) · 2022Article
- Considerations for Improving Metabolism Predictions forFrontiers in toxicology · 2022Review
- Hepatotoxicity induced by nanomaterials: mechanisms and in vitro models.Archives of toxicology · 2021Review
- The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates.Frontiers in pharmacology · 2021Review
- Novel insights into the organic solute transporter alpha/beta, OSTα/β: From the bench to the bedside.Pharmacology & therapeutics · 2020Review
- Mechanistic Modeling of the Hepatic Disposition of Estradiol-17Drug metabolism and disposition: the biological fate of chemicals · 2020Article
- Metformin Disrupts Bile Acid Efflux by Repressing Bile Salt Export Pump Expression.Pharmaceutical research · 2020Article
- Optimization of Canalicular ABC Transporter Function in HuH-7 Cells by Modification of Culture Conditions.Drug metabolism and disposition: the biological fate of chemicals · 2019Article
- Evaluation of Drug Biliary Excretion Using Sandwich-Cultured Human Hepatocytes.European journal of drug metabolism and pharmacokinetics · 2019Review
- Quantitative Systems Toxicology Analysis of In Vitro Mechanistic Assays Reveals Importance of Bile Acid Accumulation and Mitochondrial Dysfunction in TAK-875-Induced Liver Injury.Toxicological sciences : an official journal of the Society of Toxicology · 2019Article
- Novel in Vitro Method Reveals Drugs That Inhibit Organic Solute Transporter Alpha/Beta (OSTα/β).Molecular pharmaceutics · 2019Article
- Transporters in Drug Development: 2018 ITC Recommendations for Transporters of Emerging Clinical Importance.Clinical pharmacology and therapeutics · 2018Review
- Farnesoid X Receptor Agonists Obeticholic Acid and Chenodeoxycholic Acid Increase Bile Acid Efflux in Sandwich-Cultured Human Hepatocytes: Functional Evidence and Mechanisms.The Journal of pharmacology and experimental therapeutics · 2018Article
- Organic solute transporter OSTα/β is overexpressed in nonalcoholic steatohepatitis and modulated by drugs associated with liver injury.American journal of physiology. Gastrointestinal and liver physiology · 2018Article
- In vitro to in vivo extrapolation for high throughput prioritization and decision making.Toxicology in vitro : an international journal published in association with BIBRA · 2018Review
- Opportunities and challenges in the wider adoption of liver and interconnected microphysiological systems.Experimental biology and medicine (Maywood, N.J.) · 2017Review
- Prediction of Hepatic Efflux Transporter-Mediated Drug Interactions: When Is it Optimal to Measure Intracellular Unbound Fraction of Inhibitors?Journal of pharmaceutical sciences · 2017Article
- Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors.Toxicological sciences : an official journal of the Society of Toxicology · 2017Article
- Inhibition of bile salt transport by drugs associated with liver injury in primary hepatocytes from human, monkey, dog, rat, and mouse.Chemico-biological interactions · 2016Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The bile salt export pump (BSEP) plays an important role in bile acid excretion. Impaired BSEP function may result in liver injury. Bile acids also undergo basolateral efflux, but the relative contributions of biliary (CLBile) versus basolateral efflux (CLBL) clearance to hepatocellular bile acid excretion have not been determined. In the present study, taurocholic acid (TCA; a model bile acid) disposition was characterized in human and rat sandwich-cultured hepatocytes (SCH) combined with pharmacokinetic modeling. In human SCH, biliary excretion of TCA predominated (CLBile = 0.14 ± 0.04 ml/min per g liver; CLBL = 0.042 ± 0.019 ml/min per g liver), whereas CLBile and CLBL contributed approximately equally to TCA hepatocellular excretion in rat SCH (CLBile = 0.34 ± 0.07 ml/min per g liver; CLBL = 0.26 ± 0.07 ml/min per g liver). Troglitazone decreased TCA uptake, CLBile, and CLBL; membrane vesicle assays revealed for the first time that the major metabolite, troglitazone sulfate, was a noncompetitive inhibitor of multidrug resistance-associated protein 4, a basolateral bile acid efflux transporter. Simulations revealed that decreased CLBile led to a greater increase in hepatic TCA exposure in human than in rat SCH. A decrease in both excretory pathways (CLBile and CLBL) exponentially increased hepatic TCA in both species, suggesting that 1) drugs that inhibit both pathways may have a greater risk for hepatotoxicity, and 2) impaired function of an alternate excretory pathway may predispose patients to hepatotoxicity when drugs that inhibit one pathway are administered. Simulations confirmed the protective role of uptake inhibition, suggesting that a drug's inhibitory effects on bile acid uptake also should be considered when evaluating hepatotoxic potential. Overall, the current study precisely characterized basolateral efflux of TCA, revealed species differences in hepatocellular TCA efflux pathways, and provided insights about altered hepatic bile acid exposure when multiple transport pathways are impaired.
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