ArticleArchives of toxicology2022
Population pharmacokinetic model to generate mechanistic insights in bile acid homeostasis and drug-induced cholestasis.
Article in Archives of toxicology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 10 citations in OpenAlex.
- Selenium pretreatment alleviates ANIT-induced cholestasis by preserving BSEP expression and hepatic redox homeostasis.Molecular biology reports · 2026Article
- Prediction of bile salt export pump inhibition using biomimetic chromatographic descriptors: Integrating membrane affinity and protein binding.ADMET & DMPK · 2026Article
- Predicting Systemic and Liver Bosentan Exposure Using Physiologically-Based Pharmacokinetic Modeling.CPT: pharmacometrics & systems pharmacology · 2025Article
- Application of physiologically based (PBK) modeling to quantify the effect of the antibiotic tobramycin on bile acid levels in human plasma.Archives of toxicology · 2025Article
- Advances in drug-induced liver injury research: in vitro models, mechanisms, omics and gene modulation techniques.Cell & bioscience · 2024Review
- From hazard to risk prioritization: a case study to predict drug-induced cholestasis using physiologically based kinetic modeling.Archives of toxicology · 2024Article
- Use of Physiologically Based Kinetic Modeling to Predict Deoxynivalenol Metabolism and Its Role in Intestinal Inflammation and Bile Acid Kinetics in Humans.Journal of agricultural and food chemistry · 2024Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Bile acids (BA) fulfill a wide range of physiological functions, but are also involved in pathologies, such as cholestasis. Cholestasis is characterized by an intrahepatic accumulation of BAs and subsequent spillage to the systemic circulation. The aim of the present study was to develop physiologically based kinetic (PBK) models that would provide a tool to predict dose-dependent BA accumulation in humans upon treatment with a Bile Salt Export Pump (BSEP) inhibitor. We developed a PBK model describing the BA homeostasis using glycochenodeoxycholic acid as an exemplary BA. Population wide distributions of BSEP abundances were incorporated in the PBK model using Markov Chain Monte Carlo simulations, and alternatively the total amount of BAs was scaled empirically to describe interindividual differences in plasma BA levels. Next, the effects of the BSEP inhibitor bosentan on the BA levels were simulated. The PBK model developed adequately predicted the in vivo BA dynamics. Both the Markov Chain Monte Carlo simulations based on a distribution of BSEP abundances and empirical scaling of the total BA pool readily described the variations within and between data in human volunteers. Bosentan treatment disproportionally increased the maximum BA concentration in individuals with a large total BA pool or low BSEP abundance. Especially individuals having a large total BA pool size and a low BSEP abundance were predicted to be at risk for rapid saturation of BSEP and subsequent intrahepatic BA accumulation. This model provides a first estimate of personalized safe therapeutic external dose levels of compounds with BSEP-inhibitory properties.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.