Related Experiment Video
Updated: Jun 26, 2025
11:06
Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
4.4K
From hazard to risk prioritization: a case study to predict drug-induced cholestasis using physiologically based
Véronique M P de Bruijn1, Ivonne M C M Rietjens2
1Division of Toxicology, Wageningen University and Research, Wageningen, The Netherlands.
Archives of Toxicology
|May 16, 2024
Summary
A new physiologically based kinetic (PBK) model predicts drug-induced cholestasis by assessing bile acid accumulation. This approach identifies individuals at higher risk due to factors like slow drug clearance or reduced bile salt export pump (BSEP) function.
Area of Science:
- Pharmacology
- Toxicology
- Drug Metabolism
Background:
- Cholestasis involves bile acid buildup in the liver, but clinical symptoms are rare.
- Predicting drug-induced cholestasis from bile acid efflux inhibition is challenging.
Purpose of the Study:
- Develop a New Approach Methodology (NAM) to predict drug-induced cholestasis.
- Assess drug effects on hepatic bile acid efflux and accumulation.
Main Methods:
- Utilized a physiologically based kinetic (PBK) drug model to predict hepatic drug concentrations.
- Incorporated drug effects on bile acid efflux into a PBK model for bile acids.
- Used predicted bile acid accumulation to quantify cholestatic potency.
Main Results:
- Drug cholestasis incidence correlated better with internal hepatic drug concentration (AUC) above inhibition constant (Ki) than Ki alone.
- Identified risk factors: slower drug clearance, larger bile acid pool, reduced bile salt export pump (BSEP) abundance, and higher doses.
- Validated drug classifications (common, rare, no cholestasis) against model predictions.
Conclusions:
- Physiologically based kinetic (PBK) modeling provides a proof-of-principle for prioritizing cholestasis risk.
- This NAM can identify individual risk factors for drug-induced cholestasis.
- The model aids in understanding cholestasis mechanisms related to transporter inhibition.
Related Concept Videos
01:07Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance
38
Drug transporters are critical in drug absorption, distribution, and excretion processes. They should be included in physiological-based pharmacokinetic (PBPK) models, which help predict human drug disposition. However, predicting this is challenging during drug development, especially when liver transport is involved. However, with a realistic representation of body transport processes, an accurate model may be possible.
A recent model describes pravastatin's hepatobiliary excretion,...
A recent model describes pravastatin's hepatobiliary excretion,...
38
01:26Pharmacokinetic Models: Comparison and Selection Criterion
69
Physiological and compartmental models are valuable tools used in studying biological systems. These models rely on differential equations to maintain mass balance within the system, ensuring an accurate representation of the dynamic processes at play.
Physiological models take a detailed approach by considering specific molecular processes. They can predict drug distribution, metabolism, and elimination changes, providing a comprehensive understanding of how drugs interact with the body.
Physiological models take a detailed approach by considering specific molecular processes. They can predict drug distribution, metabolism, and elimination changes, providing a comprehensive understanding of how drugs interact with the body.
69
01:20Pharmacokinetic Models: Overview
665
Pharmacokinetic models utilize mathematical analysis to achieve a detailed quantitative understanding of a drug's life cycle within the body. They are instrumental in simulating a drug's pharmacokinetic parameters, predicting drug concentrations over time, optimizing dosage regimens, linking concentrations with pharmacologic activity, and estimating potential toxicity.
There are three primary types of models: empirical, compartment, and physiological. Empirical models, with minimal...
There are three primary types of models: empirical, compartment, and physiological. Empirical models, with minimal...
665
01:13Physiological Pharmacokinetic Models: Assumption with Protein Binding
41
Physiological models with protein binding in pharmacokinetics offer a sophisticated approach to understanding drug disposition. These models consider drug-protein interactions, enabling them to effectively predict drug concentrations in different organs and tissues. This precision aids in accurate drug dosing, providing a significant advantage over conventional models. A key process within these models is equilibration, which ensures that drug concentrations achieve a steady state within the...
41
01:21Mechanistic Models: Overview of Compartment Models
83
Mechanistic models, a category encompassing both physiological and compartmental modeling, differ from empirical models' approaches to incorporating known factors about the systems being modeled. Empirical models describe data with minimal assumptions, while mechanistic models aim to provide a robust description of available data by specifying assumptions and integrating known factors about the system. Compartmental analysis is a key example of a mechanistic model in pharmacokinetics and...
83
01:15Model Approaches for Pharmacokinetic Data: Physiological Models
42
Physiological models in pharmacokinetics are instrumental in understanding the distribution and elimination of drugs within the body. These models describe the drug concentration within target organs, influenced by factors such as drug uptake, tissue volume, and blood flow. Drug uptake is governed by the partition coefficient, which signifies the drug concentration ratio in tissue to that in the blood. The blood flow rate to a specific tissue is expressed as Qt, and the rate of change in tissue...
42