1. Integration of a physiologically-based pharmacokinetic model with a whole-body, organ-resolved genome-scale model for characterization of ethanol and acetaldehyde metabolism
- Author
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William Pei, Radhakrishnan Mahadevan, Leo Zhu, and Ines Thiele
- 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 - 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., 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.
- Published
- 2021