Academic journal article Alcohol Research

Studying Alcohol Elimination Using the Alcohol Clamp Method

Academic journal article Alcohol Research

Studying Alcohol Elimination Using the Alcohol Clamp Method

Article excerpt

Researchers studying alcohol absorption and metabolism in humans have been aided by the alcohol clamp method, in which alcohol is administered intravenously, allowing study participants to achieve and maintain a target breath alcohol concentration (BrAC) for an extended period of time. This tool minimizes the variability in BrACs that occurs after alcohol consumption by administering alcohol at a dose and rate that is computed for each person individually. The alcohol clamp can be used to evaluate several influences on alcohol elimination, including gender, ethnicity, genetic variations in alcohol-metabolizing enzymes, and food consumption. KEY WORDS: alcohol absorption; ethanol metabolism; alcohol clamp method; alcohol elimination; alcohol elimination rate (AER); breath alcohol concentration (BrAC); intravenous infusion; pharmacokinetics; pharmacodynamics; Michaelis-Menten kinetics; alcohol dehydrogenase (ADH); acetaldehyde dehydrogenase (ALDH); genetic polymorphisms; liver; food intake

Multiple factors can influence breath alcohol concentration (BrAC)1 after alcohol use. To minimize the variability in BrACs that occurs in human research study participants after ingestion of alcohol, researchers developed an alcohol "clamping" method in which alcohol is administered intravenously to achieve and maintain a prescribed target BrAC. Individuals vary as much as three- to four-fold in the absorption, distribution, and metabolism of even a standardized oral dose of alcohol (Friel et al. 1995; Li et al. 1998). Many factors contribute to this variability, including those that can be controlled during an experiment such as the rate of input, type, concentration, and volume of alcoholic beverage consumed, and food intake (Dubowski 1985; Sedman et al. 1976). Other factors that are less controllable include first-pass metabolism of alcohol by the gut and liver prior to distribution into the bloodstream, anatomic and physiological variation in stomach (i.e., gastric) emptying, liver volume and blood flow, genetics, ethnicity, gender, age, and drinking history (Marshall et al. 1983; Li et al. 1998; Pikaar et al. 1988).

The alcohol clamp was developed to allow researchers to maintain a target BrAC in study participants despite these factors. With this research method, alcohol is intravenously administered (i.e., infused) for a prolonged, predetermined period of time (O'Connor et al. 1998; Ramchandani et al. 2006). Figure 1A shows a typical alcohol clamp, in which a target BrAC of 60 mg% (60 mg of ethanol in a 10th of a liter of fluid; 0.06 percent in terms related to automobile driving standards) is achieved in 10 minutes following the start of the infusion and then maintained at that level for 170 minutes. The desired BrAC exposure is achieved by administering alcohol according to a specific dosage and rate (i.e., infusion rate profile) (Figure 1B) that is pre-computed for each individual by estimating physiological parameters that include his or her specific alcohol elimination rate (AER). Researchers make this estimate using a computer model that describes what happens to a chemical in the body (i.e., a physiologically based pharmacokinetic [PBPK] model) for alcohol (Ramchandani et al. 1999; Plawecki et al. 2004). The model's parameters are estimated for each subject, based on the individual's age, height, weight, and gender. Using these estimates, a PBPK model-based algorithm computes the infusion rate profile for any desired BrAC exposure to be achieved during the experiment (for details of algorithm, please see Ramchandani et al. 1999 and O'Connor et al. 2000). The infusion profile, when administered to the study participant, yields the desired time course of BrAC. Ensuring that the target BrAC is accurately maintained requires minor real-time adjustments to the infusion rate profile. Such adjustments are based on serial breath alcohol measurements and are necessary in order to obtain BrACs that remain within 5 mg% of target levels (O'Connor et al. …

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