Pharmacokinetics Of Alcohol (Encyclopedia of Drugs, Alcohol, and Addictive Behavior)
The discipline known as pharmacokinetics deals with the way drugs are absorbed, distributed, and eliminated by the body and how these processes can be described in quantitative terms. The pharmacokinetics of alcohol (ethyl alcohol or ethanol) is an important issue in forensic toxicology and clinical medicine, when the amount of alcohol in the body is estimated from the concentration measured in a blood sample.
The Swedish scientist Erik M.P. Widmark (1889-1945) made pioneer contributions to knowledge about the pharmacokinetics of ethanol during the early decades of the twentieth century. Widmark observed that after the peak concentration in blood had been reached, the disappearance phase seemed to follow a near straight-line course, suggesting that the system for metabolizing alcohol was saturated (fully occupied), so that the amount of alcohol metabolized each hour did not depend on the amount in the blood. This situation is termed a zero-order elimination process. (Zero-order kinetics is contrasted with first-order kinetics, in which the metabolic system [e.g., the liver] is not saturated and in which the amount of drug metabolized per hour increases as the amount presented to the metabolic system increases.) Figure 1 (left
Zero-order kinetics implies that the elimination rate of ethanol is independent of the BLOOD ALCOHOL CONCENTRATION (BAC) and therefore ko should be the same regardless of the dose of ethanol administered; however, more recent studies have show that the slope of the BAC decay phase is steeper after larger doses of ethanol are ingested. Furthermore, when the BAC declines below about 10 mg/dl (0.01 g%, 2.17 mmol/l) the elimination curve of ethanol from blood flattens out and changes into a curvilinear decay profile.
Two different methods are described in the literature to portray the pharmacokinetics of ethanol. The method of choice seems to depend on the professional interests, the scientific background, and the training of those concerned. Specialists in forensic medicine and toxicology, as well as other disciplines, favor the mathematical approach developed by Widmark. In contrast, scientists with their basic training in pharmacy and pharmacology prefer Michaelis-Menten (MM) kinetics, that is, saturable or capacity-limited enzyme kinetics. The MM model is depicted in Figure 1 (right frame) after intravenous input of ethanol. A pseudolinear phase is evident for most of the elimination profile, provided that the BAC remains sufficiently high (>10 mg/dl). At low substrate concentrations (C), a hockey-stick shape develops when data are plotted on cartesian graph paper. Accordingly, when C is much greater than km, the elimination rate approaches its maximum velocity; dC/dt Vmax (Figure 1, right frame). When C is less than km the elimination rate is proportional to the substrate concentration; dC/dt (Vmax/km) C and the MM equation collapses into first-order kinetics. This collapsing of the model is a consequence of capacity-limited kinetics and does not reflect any sudden change in the order of the biochemical reaction.
ETHANOL AS A DRUG
Ethanol differs from most other drugs in the way it is absorbed into the blood, metabolized in the liver, and how it enters the brain and produces its pharmacological effect. Ethanol (CH3CH2OH) has a molecular weight of 46.05, mixes with water in all proportions and carries only a weak charge; this means that the molecules of ethanol easily pass through biological membranes, including the blood-brain barrier. After absorption into the portal blood, ethanol passes through the liver, where enzymes begin the conversion into acetaldehyde and acetate. The end products of ethanol metabolism are carbon dioxide and water. The concentrations of ethanol in biological specimens depend on the dose ingested, the time after drinking, and the water content of the materials analyzed. The concentration-time profiles of ethanol and the pharmacokinetic parameters will differ depending on whether plasma, serum, urine, or saliva are the specimens analyzed. Several detailed reviews of ethanol pharmacokinetics are available and included in the bibliography.
Information about the absorption kinetics of ethanol is much less extensive than that about elimination kinetics. Unlike most other drugs, the dose of ethanol is not swallowed instantaneously because the drinking is usually spread over a period of time. For research purposes, however, ingestion of a bolus dose usually infers drinking times of five to fifteen minutes. The dosage form of ethanol, whether ingested as beer (3-6% w/v), wine (9-12% w/v), spirits (32-40% w/v), or as a cocktail (15-25% w/v) might influence the pharmacokinetic parameters. Absorption of ethanol starts in the stomach where about 20 percent of the dose can become absorbed. The remainder is absorbed from the upper part of the small intestine. The speed of absorption of alcohol depends to a large extent on the rate of gastric emptying, which varies widely among different subjects. Assuming that the rate of absorption from the gut is a first-order process, one can represent the entire concentration-time profile of ethanol with a single equation: Where C=BAC at some time t after administration Co=Initial BAC extrapolated BAC (see Figure 2) k=First-order absorption rate constant ko=Zero-order elimination rate constant t=Time after drinking The peak BAC and the time of reaching the peak after drinking are important aspects of the absorption kinetics. Table 1 gives examples of these parameters after healthy men drank neat whiskey (40% v/v or 80 proof) on an empty stomach. The absorption of ethanol occurs more slowly from the stomach than from the intestine owing to the enormous difference in the absorption surface available. Factors that influence gastric emptying, such as food in the stomach before drinking, will alter the rate of absorption and the peak BAC reached. The absorption of ethanol occurs progressively during a drinking binge or spree, and studies have shown that the BAC fifteen minutes after the last drink has reached about 80 percent of the final peak BAC. Because of the saturation-type kinetics, the peak BAC and the area under the curve (AUC) increase more than expected from proportional increases in the dose. The slower the rate of delivery of ethanol to the liver the smaller the AUC for a given dose and vice versa. The systemic availability (bioavailability) of drugs like ethanol with dose-dependent kinetics should not be calculated from the ratio of AUC after oral and intravenous administration.
THE WIDMARK EQUATION
Figure 2 gives examples of the concentration-time profiles of ethanol obtained from oral and intravenous administration of a moderate dose. The ratio of the dose administered (D) to the initial extrapolated concentration of ethanol in blood (C0) is the apparent volume of distribution (Vd) having dimensions L/kg. This defines the relationship between the concentration of ethanol spread over the body weight (in kilograms, kg) and the concentration in the blood.
Equation  is known as the Widmark equation;it is widely used to estimate alcohol in the body from measurements of alcohol in the blood. Widmark found that the average Vd for men was 0.68, with a range from 0.51-0.85, but in women the volume of distribution was lessith an average of 0.55 and a range of 0.44-0.66. These differences between the sexes stem from differences in body-tissue composition; proportionally, women carry more fat but less water than do men. Accordingly, women reach higher BACs than men if the same dose of ethanol is given according to body weight. A similar observation was made in studies of men with widely different ages, because body water decreases in the elderly. By dividing the dose of ethanol administered (g/kg) by the time needed to reach zero BAC (time0) one obtains an estimate of the rate of clearance of ethanol from the body. This calculation neglects the nonlinear phase of ethanol elimination beginning at BAC below 10 mg/dl but does include the contribution from any first-pass metabolism occurring in the liver and gut.
If equation  is combined with the expression for zero-order elimination kinetics (C C0 k0t) rearrangement gives equations  and : or
Equation  can be used to estimate the amount (dose D) of alcohol a person has consumed from knowledge of his or her BAC (C). Similarly, equation  allows estimating the BAC (C) that might exist after drinking a known amount of ethanol. For best results when using these equations, absorption and distribution of ethanol must be complete at the time of sampling blood. Owing to inter- and intra-individual variations in the pharmacokinetic parameters Vd and k0 the results obtained are subject to considerable uncertainty. This uncertainty should be allowed for when these calculations are made for legal purposes, for example, in trials concerned with DRIVING UNDER THE INFLUENCE of alcohol. A variability of 20 percent seems appropriate for most situations.
RESEARCH ON ADH
The enzymes responsible for ethanol oxidation are mostly located in the liver, but recent research has focused on the existence of alcohol dehydrogenase (ADH)he enzyme that transforms alcohol to acetaldehyden the gastrointestinal mucosa. Gastric ADH seems to be less effective in oxidizing ethanol in women (than in men) and in alcoholics (than in moderate drinkers). When a moderate dose of ethanol was ingested on an empty stomach, first-pass metabolism was negligible. This was explained by the ethanol bypassing gastric ADH, owing to rapid absorption occurring. However, the quantitative significance of gut metabolism in the overall disposal of ethanol remains controversial.
ELIMINATION RATES AND ENZYMES
Differences in the rate of disappearance of ethanol from blood might depend on genetic and environmental factors influencing an individual's catalytic activity of alcohol-metabolizing enzymes. In humans, the enzyme ADH occurs in multiple molecular forms, designated class I, II, and III. Class I enzymes are located mainly in the liver cytosol and have a low km for ethanol. Various isozymes (variations within a class) exist and β1-ADH (class I) is predominant in Caucasians whereas β2-ADH (class II) is the most abundant isozyme in Asians. The rate of ethanol elimination in the various racial groups is not much different from the variations seen within a single racial group in well-designed studies that allow for racial differences in body compositionhe proportion of fat to lean body mass.
Alcoholics have a greater capacity to eliminate ethanol than do moderate drinkers. Disappearance rates from blood of 30 mg/dl/h are not uncommonompared with a mean rate of only 15 mg/dl/h (range 8-20 mg/dl/h) in moderate drinkers. The liver microsomes contain enzymes capable of oxidizing ethanol as well as other drugs, organic solvents, and environmental chemicals. One particular form of the cytochrome P450 enzyme (denoted P450IIEI) metabolizes ethanol. This microsomal ethanol oxidizing system (MEOS) has a km of 40-60 mg/dl (8.7-13 mmol/l) compared with 2-5 mg/dl (0.4-1 mmol/l) for human ADH. More importantly, the P450IIEI isozyme becomes more active during prolonged exposure to ethanol process known as enzyme induction. Accordingly, because of continuous heavy drinking, alcoholics develop a high capacity for eliminating ethanol from the blood. Their enhanced capacity vanishes after a short period of abstinence, however, but liver disease (hepatitis, cirrhosis) in alcoholics does not seem to impair their ability to dispose of ethanol.
BEHAVIORAL EFFECTS OF ALCOHOL
Studies have shown that the behavioral effects of ethanol and its associated impairment of performance are more pronounced when the BAC is rising than when it is falling. This observation seems to depend, at least in part, on the distribution of ethanol between blood and tissue. The arterial blood concentration of ethanol is pumped to the brain and this exceeds the concentration measured in the venous blood, which is returning to the heart from skeletal muscles. This arterio-venous difference is most pronounced shortly after drinking; it decreases as ethanol diffuses equally into all body fluids. It seems that this is not the whole story, because some evidence points to the development of acute cellular tolerance to ethanol's effectsn aspect of tolerance that quickly develops.
Despite extensive studies of ethanol pharmacokinetics spanning many years, there are still a number of unsettled issues and areas of debate. Two such issues are (1) the practical advantages of Michaelis-Menten kinetics as opposed to Widmark's zero-order model and (2) the role of gastric ADH in presystemic disposal of ethanol. The importance of blood source (artery, capillary, or vein) and the sampling site (arm or leg) on ethanol pharmacokinetics deserves further study, as does whether multicompartmental models should be invoked.
(SEE ALSO: Accidents and Injuries from Alcohol; Addiction: Concepts and Definitions; Alcohol; Chinese Americans, Alcohol and Drug Use among; Drug Interactions and Alcohol; Drug Metabolism; Drunk Driving; Psychomotor Effects of Alcohol and Drugs; Vulnerability As Cause of Substance Abuse)
HOLFORD, N. H. G. (1987). Clinical pharmacokinetics of ethanol. Clinical Pharmacokinetics 13, 273-292.
VON WARTBURG, J. P. (1989). Pharmacokinetics of Alcohol. In K. E. Crow & R. D. Batt (Eds.), Human metabolism of alcohol. Boca Raton, FL: CRC Press.
WIDMARK, E. M. P. (1981). Principles and applications of medicolegal alcohol determination. Davis, CA: Biomedical Publications. (English translation of Widmark's 1932 monograph, in German)
WILKINSON, P. K. (1980). Pharmacokinetics of ethanol: A review. Alcoholism: Clinical and Experimental Research 4, 6-21.
A. W. JONES