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Integration of a physiologically-based pharmacokinetic model with a whole-body, organ-resolved genome-scale model for characterization of ethanol and acetaldehyde metabolism
- Source :
- PLoS Computational Biology, Vol 17, Iss 8, p e1009110 (2021), PLoS Computational Biology
- Publication Year :
- 2021
- Publisher :
- Public Library of Science (PLoS), 2021.
-
Abstract
- Ethanol is one of the most widely used recreational substances in the world and due to its ubiquitous use, ethanol abuse has been the cause of over 3.3 million deaths each year. In addition to its effects, ethanol’s primary metabolite, acetaldehyde, is a carcinogen that can cause symptoms of facial flushing, headaches, and nausea. How strongly ethanol or acetaldehyde affects an individual depends highly on the genetic polymorphisms of certain genes. In particular, the genetic polymorphisms of mitochondrial aldehyde dehydrogenase, ALDH2, play a large role in the metabolism of acetaldehyde. Thus, it is important to characterize how genetic variations can lead to different exposures and responses to ethanol and acetaldehyde. While the pharmacokinetics of ethanol metabolism through alcohol dehydrogenase have been thoroughly explored in previous studies, in this paper, we combined a base physiologically-based pharmacokinetic (PBPK) model with a whole-body genome-scale model (WBM) to gain further insight into the effect of other less explored processes and genetic variations on ethanol metabolism. This combined model was fit to clinical data and used to show the effect of alcohol concentrations, organ damage, ALDH2 enzyme polymorphisms, and ALDH2-inhibiting drug disulfiram on ethanol and acetaldehyde exposure. Through estimating the reaction rates of auxiliary processes with dynamic Flux Balance Analysis, The PBPK-WBM was able to navigate around a lack of kinetic constants traditionally associated with PK modelling and demonstrate the compensatory effects of the body in response to decreased liver enzyme expression. Additionally, the model demonstrated that acetaldehyde exposure increased with higher dosages of disulfiram and decreased ALDH2 efficiency, and that moderate consumption rates of ethanol could lead to unexpected accumulations in acetaldehyde. This modelling framework combines the comprehensive steady-state analyses from genome-scale models with the dynamics of traditional PK models to create a highly personalized form of PBPK modelling that can push the boundaries of precision medicine.<br />Author summary Alcohol is a widely used recreational drug in many parts of the world and it is often abused or misused, leading to the deaths of millions of people each year from driving under the influence and overdose. Additionally, the body breaks down alcohol into acetaldehyde, a carcinogen that has its own effects ranging from headaches and nausea to liver damage. The effects of ethanol and acetaldehyde vary due to genetic variations that create different forms of the enzymes responsible for breaking them down. Due to these differences, it is important to characterize how these changes affect the metabolism of alcohol and acetaldehyde. To capture these differences, we have created a new model that integrates the traditional pharmacokinetic model with a whole-body genome-scale model that can characterize different genetic variations. In addition, traditional models often require experimentally measured data, yet with this new framework we avoid this tedious process by mathematically solving the genome-scale model with the dynamic Flux Balance Analysis technique, allowing for gap filling. Through this model, we show that the whole-body genome-scale model demonstrates flexibility and robustness that has not been seen before in pharmacokinetic models. Our model combines advantages from both pharmacokinetic and genome-scale modelling and can be personalized to characterize individual reactions to other drugs and further precision medicine.
- Subjects :
- Male
Enzyme Metabolism
Alcohol
Pharmacology
Biochemistry
chemistry.chemical_compound
0302 clinical medicine
Drug Metabolism
Disulfiram
Medicine and Health Sciences
Metabolites
Tissue Distribution
Biology (General)
Enzyme Chemistry
0303 health sciences
Alcohol Consumption
Ecology
biology
Organic Compounds
Aldehyde Dehydrogenase, Mitochondrial
3. Good health
Enzymes
Alcoholism
Chemistry
Computational Theory and Mathematics
Liver
Modeling and Simulation
Physical Sciences
medicine.drug
Research Article
Physiologically based pharmacokinetic modelling
QH301-705.5
Acetaldehyde Dehydrogenase Inhibitors
Acetaldehyde
Models, Biological
03 medical and health sciences
Cellular and Molecular Neuroscience
Genetics
medicine
Humans
Computer Simulation
Pharmacokinetics
Ethanol metabolism
Molecular Biology
Ecology, Evolution, Behavior and Systematics
030304 developmental biology
Alcohol dehydrogenase
ALDH2
Nutrition
Ethanol
Organic Chemistry
Chemical Compounds
Computational Biology
Biology and Life Sciences
Proteins
Diet
Kinetics
Metabolism
chemistry
Intestinal Absorption
Alcohols
biology.protein
Enzymology
030217 neurology & neurosurgery
Alcohol Deterrents
Subjects
Details
- Language :
- English
- ISSN :
- 15537358
- Volume :
- 17
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- PLoS Computational Biology
- Accession number :
- edsair.doi.dedup.....77086f16f248e0ad9a615b8ab4e6032f