The
pharmacokinetics of ethanol are well characterized by the
ADME acronym (absorption, distribution, metabolism, excretion). Besides the dose ingested, factors such as the person's
total body water, speed of drinking, the drink's nutritional content, and the contents of the stomach all influence the profile of
blood alcohol content (BAC) over time. Breath alcohol content (BrAC) and BAC have similar profile shapes, so most forensic pharmacokinetic calculations can be done with either. Relatively few studies directly compare BrAC and BAC within subjects and characterize the difference in pharmacokinetic parameters. Comparing arterial and venous BAC, arterial BAC is higher during the absorption phase and lower in the postabsorptive declining phase.
glycerolipid metabolism, and
bile acid biosynthesis pathways.
Fermentation is a biochemical process during which yeast and certain bacteria convert sugars to ethanol, carbon dioxide, as well as other metabolic byproducts. The average human digestive system produces approximately 3g of ethanol per day through fermentation of its contents. Such production generally does not have any forensic significance because the ethanol is broken down before significant intoxication ensues. These trace amounts of alcohol range from 0.1 to in the blood of healthy humans, with some measurements as high as .
Auto-brewery syndrome is a condition characterized by significant fermentation of ingested carbohydrates within the body. In rare cases, intoxicating quantities of ethanol may be produced, especially after eating meals. Claims of endogenous fermentation have been attempted as a defense against drunk driving charges, some of which have been successful, but the condition is under-researched.
Absorption s at a festival in Hungary. Carbonated alcoholic drinks seem to be absorbed faster. Ethanol is most commonly ingested by mouth, but other
routes of administration are possible, such as
inhalation,
enema, or by
intravenous injection. The absorption rate of ethanol is typically modeled as a first-order kinetic process depending on the concentration gradient and specific membrane. The rate of absorption is fastest in the duodenum and jejunum, owing to the larger absorption surface area provided by the villi and microvilli of the small intestines.
Gastric emptying is therefore an important consideration when estimating the overall rate of absorption in most scenarios; In humans, concentrations of ethanol in air above 10 mg/L caused initial coughing and smarting of the eyes and nose, which went away after adaptation. 20 mg/L was just barely tolerable. Concentrations above 30 mg/L caused continuous coughing and tears, and concentrations above 40 mg/L were described as intolerable, suffocating, and impossible to bear for even short periods. Breathing air with concentration of 15 mg/L ethanol for 3 hours resulted in BACs from 0.02 to 0.45 g/L, depending on breathing rate. It is not a particularly efficient or enjoyable method of becoming intoxicated. Applying a 70% ethanol solution to a skin area of for 1 hr would result in approximately of ethanol being absorbed. The substantially increased levels of ethanol in the blood reported for some experiments are likely due to inadvertent inhalation. Ethanol is rapidly absorbed through cut or damaged skin, with reports of ethanol intoxication and fatal poisoning. The timing of peak blood concentration varies depends on the type of alcoholic drink: •
Vodka tonic: 36 ± 10 minutes after consumption • Wine: 54 ± 14 minutes • Beer: 62 ± 23 minutes Also, carbonated alcoholic drinks seem to have a shorter onset compare to flat drinks in the same volume. One theory is that carbon dioxide in the bubbles somehow speeds the flow of alcohol into the intestines. Absorption is reduced by a large meal. Stress speeds up absorption.
Distribution After absorption, the alcohol goes through the
portal vein to the liver, then through the
hepatic veins to the heart, then the
pulmonary arteries to the lungs, then the
pulmonary veins to the heart again, and then enters
systemic circulation. Once in systematic circulation, ethanol
distributes throughout the body,
diffusing passively and crossing all
biological membranes including the
blood–brain barrier. At equilibrium, ethanol is present in all body fluids and tissues in proportion to their water content. Ethanol does not
bind to plasma proteins or other biomolecules. The rate of distribution depends on blood supply,
Peak circulating levels of ethanol are usually reached within a range of 30 to 90 minutes of ingestion, with an average of 45 to 60 minutes. and has been the subject of much research. Widmark originally used units of mass (g/kg) for EBAC, thus he calculated the apparent of distribution or mass of blood in kilograms. He fitted an equation M_d=\rho_m W of the body weight in kg, finding an average rho-factor of 0.68 for men and 0.55 for women. This has units of dose per body weight (g/kg) divided by concentration (g/kg) and is therefore dimensionless. However, modern calculations use weight/volume concentrations (g/L) for EBAC, so Widmark's rho-factors must be adjusted for the density of blood, 1.055 g/mL. This \rho_v = V_d / W has units of dose per body weight (g/kg) divided by concentration (g/L blood) - calculation gives values of 0.64 L/kg for men and 0.52 L/kg for women, lower than the original. A more accurate method for calculating is to use
total body water (TBW) - experiments have confirmed that alcohol distributes almost exactly in proportion to TBW within the Widmark model. TBW may be calculated using
body composition analysis or estimated using anthropometric formulas based on age, height, and weight. is then given by TBW_\text{kg} / F_{\text{water}}, where F_{\text{water}} is the water content of blood, approximately 0.825 w/v for men and 0.838 w/v for women. These calculations assume Widmark's zero-order model for the effects of metabolization, and assume that TBW is almost exactly the volume of distribution of ethanol. Using a more complex model that accounts for non-linear metabolism, Norberg found that Vd was only 84-87% of TBW. This finding was not reproduced in a newer study which found volumes of distribution similar to those in the literature. At even low physiological concentrations, ethanol completely saturates alcohol dehydrogenase. If catabolism of alcohol goes all the way to completion, then there is a very exothermic event yielding some of energy. If the reaction stops part way through the metabolic pathways, which happens because acetic acid is excreted in the urine after drinking, then not nearly as much energy can be derived from alcohol, indeed, only . At the very least, the theoretical limits on energy yield are determined to be to . The first with NADH is endothermic, requiring of alcohol, or about 3 molecules of
adenosine triphosphate (ATP) per molecule of ethanol.
Variation Variations in genes influence alcohol metabolism and drinking behavior. Certain amino acid sequences in the enzymes used to oxidize ethanol are conserved (unchanged) going back to the last common ancestor over 3.5bya. Evidence suggests that
humans evolved the ability to metabolize dietary ethanol between 7 and 21 million years ago, in a common ancestor shared with
chimpanzees and
gorillas but not
orangutans. Gene variation in these enzymes can lead to variation in catalytic efficiency between individuals. Some individuals have less effective metabolizing enzymes of ethanol, and can experience more marked symptoms from ethanol consumption than others. However, those having acquired
alcohol tolerance have a greater quantity of these enzymes, and metabolize ethanol more rapidly. Specifically, ethanol has been observed to be cleared more quickly by regular drinkers than non-drinkers. Food such as
fructose can increase the rate of alcohol metabolism. The effect can vary significantly from person to person, but a 100 g dose of fructose has been shown to increase alcohol metabolism by an average of 80%. In people with proteinuria and hematuria, fructose can cause falsely high BAC readings, due to kidney-liver metabolism.
First-pass metabolism During a typical drinking session, approximately 90% of the metabolism of ethanol occurs in the liver. Alcohol dehydrogenase and aldehyde dehydrogenase are present at their highest concentrations (in liver mitochondria). But these enzymes are widely expressed throughout the body, such as in the
stomach and
small intestine. Accordingly, the fetal liver cannot metabolize ethanol or other low molecular weight xenobiotics. In fetuses, ethanol is instead metabolized at much slower rates by different enzymes from the cytochrome P-450 superfamily (CYP), in particular by CYP2E1. The low fetal rate of ethanol clearance is responsible for the important observation that the fetal compartment retains high levels of ethanol long after ethanol has been cleared from the maternal circulation by the adult ADH activity in the maternal liver. CYP2E1 expression and activity have been detected in various human fetal tissues after the onset of organogenesis (ca 50 days of gestation). Exposure to ethanol is known to promote further induction of this enzyme in fetal and adult tissues. CYP2E1 is a major contributor to the so-called
Microsomal Ethanol Oxidizing System (MEOS) and its activity in fetal tissues is thought to contribute significantly to the toxicity of maternal ethanol consumption. In presence of ethanol and oxygen, CYP2E1 is known to release superoxide radicals and induce the oxidation of polyunsaturated fatty acids to toxic aldehyde products like 4-hydroxynonenal (HNE). The concentration of alcohol in breast milk produced during lactation is closely correlated to the individual's blood alcohol content.
Elimination Alcohol is removed from the bloodstream by a combination of metabolism, excretion, and evaporation. 90-98% of ingested ethanol is metabolized into carbon dioxide and water. such as SCRAM ankle bracelet or the more discreet ION Wearable. Ethanol or its metabolites may be detectable in urine for up to 96 hours (3–5 days) after ingestion. This is because typical doses of alcohol saturate the enzymes' capacity. In Widmark's model, the elimination rate from the blood, , contributes 60% of the uncertainty. Earlier studies found mean elimination rates of 15 mg/dL per hour for men and 18 mg/dL per hour for women, Explanations for the gender difference are quite varied and include liver size, secondary effects of the volume of distribution, and sex-specific hormones. A 2023 study using a more complex two-compartment model with M-M elimination kinetics, with data from 60 men and 12 women, found statistically small effects of gender on maximal elimination rate and excluded them from the final model. At concentrations below 0.15-0.20 g/L, alcohol is eliminated more slowly and the elimination rate more closely follows first-order kinetics. The overall behavior of the elimination rate is described well by
Michaelis–Menten kinetics. This change in behavior was not noticed by Widmark because he could not analyze low BAC levels. The model corresponds to a single-compartment model with instantaneous absorption and
zero-order kinetics for elimination. The model is most accurate when used to estimate BAC a few hours after drinking a single dose of alcohol in a fasted state, and can be within 20%
CV of the true value. It is less accurate for BAC levels below 0.2 g/L (alcohol is not eliminated as quickly as predicted) and consumption with food (overestimating the peak BAC and time to return to zero). == See also ==