In Silico Models of Alcohol Kinetics: A Deterministic Approach

Introduction

In recent years, the mathematical representation of physiological systems and its use in computer simulations have come of age. Initially restricted to pharmacokinetics and pharmacodynamics studies, they are now used in many different fields of medicine (e.g., diabetes and metabolic syndrome) to explore previously inaccessible metabolic markers, develop candidate treatments, and even to obtain authorization of regulatory agencies for clinical research, thereby bypassing animal testing. The field of alcohol addiction is of particular interest for such applications: it is both very developed (e.g., in modeling the dynamics of ethanol in blood or the diffusion from blood to brain tissues) and in its infancy, with only two simulation studies in the past 20 years. In addition, it requires modeling of behavioral system and medication effects that are not yet mainstream (see Chapter 64 ). In this chapter, we present several published and novel models of ethanol blood distribution, leading to simulation studies linking system-level characteristics to clinical outcomes.

Mechanisms of Alcohol Intoxication

Ethyl alcohol, also known as ethanol, is the substance found in alcoholic beverages. It is a colorless liquid that mixes in all proportions with water and therefore is readily distributed throughout the body in the aqueous bloodstream after consumption. In addition, because of this water miscibility it readily crosses important biological membranes, such as the blood-brain barrier. After it reaches the brain, alcohol affects multiple molecular targets, some of which remain unknown. In particular, alcohol causes γ-aminobutyric acid (GABA) receptors to remain open longer, allowing more chloride ions to enter brain cells and, therefore, causing relaxation, sedation, and overall inhibition of brain activity. At low concentrations, alcohol sensitizes the glutamate system, which stimulates areas of the brain associated with pleasure such as the cortico-mesolimbic dopamine system. With chronic exposure to alcohol, the brain undergoes long-lasting biochemical changes including neurological adaptation of the ion channels. Alcohol is also responsible for structural changes in the brain, such as loss of neuronal mass and brain shrinkage, which, in turn, is responsible for impaired cognitive function. Of interest, the maximum quantity of alcohol consumed, such as in binge drinking, seems to be a better predictor of alcohol-related impairment. Hence, understanding the elimination process of alcohol will, to a certain degree, help us predict the extent of the neurological adaptation that takes place with chronic alcohol use.

Alcohol Metabolism

When we consume alcohol, the majority of it is absorbed from the small intestine (approximately 80%) and the stomach (approximately 20%). Generally, drinking more alcohol within a certain period of time will result in increased blood alcohol concentrations due to more alcohol being available for absorption into the bloodstream. More than 90% of the alcohol that enters the body is completely metabolized in the liver. The remaining 10% is not metabolized and is excreted in the sweat, urine, and breath. There are several routes of metabolism of alcohol in the body. The major pathways involve the liver and, in particular, the oxidation of alcohol by alcohol dehydrogenase to produce acetaldehyde, a highly toxic substance. The second step is catalyzed by acetaldehyde dehydrogenase. This enzyme converts acetaldehyde to acetic acid, a nontoxic metabolite. Acetic acid is eventually metabolized to carbon dioxide and water. Another system in the liver oxidizes ethanol via the enzyme cytochrome P450 (CYP)IIE1. This microsomal ethanol-oxidizing system seems to play a more important role at higher concentrations of ethanol.

Individual Differences in the Rate of Alcohol Metabolism

There are genetic variations in the CYPE1 enzyme system that lead to individual differences in the rate of ethanol metabolism in humans. The rate of alcohol metabolism depends, in part, on the amount of metabolizing enzymes in the liver, which varies among individuals and appears to have some genetic determinants. After the consumption of one standard drink, the amount of alcohol in the drinker’s blood usually peaks within 30–45 minutes. (A standard drink is defined as 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of 80-proof distilled spirits, all of which contain approximately the same amount of alcohol.) The concentration of alcohol in the entire body, including the brain, is always less than that in the blood; human tissues contain a much lower percentage of water compared with the blood. However, organs having a rich blood supply, such as the brain, will quickly reach alcohol diffusion equilibrium with arterial blood. This explains why most people experience intoxication very quickly after taking a couple of drinks and then sober up rapidly as other bodily tissues with less blood supply, such as the muscle, start to absorb alcohol from the blood, meaning that less alcohol is circulating in the bloodstream.

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