Ethanol pharmacokinetic metabolism

After oral ingestion, ethanol pharmacokinetics must take into account (1) Absorption from the gastrointestinal tract. Since ethanol is absorbed most efficiently from the small intestines, the rate of gastric emptying is an important factor that governs the rate of rise of blood alcohol concentration (BAC), i.e., the slope of the ascending limb of the BAC-time curve, and the extent of first pass metabolism of ethanol by the liver and stomach. (2) Distribution of ethanol in the body. Ethanol distributes equally in total body water, which is related to the lean body mass of the person, and (3) the elimination of ethanol from the body, which occurs primarily by metabolism in the liver, first to acetaldehyde and then to acetate [7]. 

Levitt, D.G., PKQuest measurement of intestinal absorption and first pass metabolism — Application to human ethanol pharmacokinetics, BMC Clin. Pharmacol, 2, 4, 2002. 

Alcohol dehydrogenase is a cytoplasmic enzyme mainly found in the liver, but also in the stomach. The enzyme accomplishes the first step of ethanol metabolism, oxidation to acetaldehyde, which is further metabolized by aldehyde dehydrogenase. Quantitatively, the oxidation of ethanol is more or less independent of the blood concentration and constant with time, i.e. it follows zero-order kinetics (pharmacokinetics). On average, a 70-kg person oxidizes about 10 ml of ethanol per hour. 

Alcohol can affect the metabolism of trichloroethylene. This is noted in both toxicity and pharmacokinetic studies. In toxicity studies, simultaneous exposure to ethanol and trichloroethylene increased the concentration of trichloroethylene in the blood and breath of male volunteers (Stewart et al. 1974c). These people also showed "degreaser s flush"—a transient vasodilation of superficial skin vessels. In rats, depressant effects in the central nervous system are exacerbated by coadministration of ethanol and trichloroethylene (Utesch et al. 1981). 

The effects of ethanol on bodily functions, e.g., those of the brain, heart, and liver, are dependent upon the systemic concentrations of ethanol over time. Therefore, the pharmacokinetics of ethanol play a pivotal role in the pharmacodynamic actions of ethanol and of its metabolic product acetaldehyde [6],... 

Pharmacokinetic and pharmacodynamic profiles of olanzapine have been extensively reviewed (266). Olanzapine does not inhibit CYP isozymes, and no clinically significant metabolic interactions were found of olanzapine with aminophylline, biperiden, diazepam, ethanol, fluoxetine, imipramine, lithium, or R/S-warfarin. 

The diverse nature of these effects is illustrated by recounting the experience of clinical pharmacologists who studied the pharmacokinetics of felodipine, a dihydropyridine calcium channel antagonist (14). They designed a study to test the effects of ethanol on felodipine metabolism. To mask the flavor of ethanol from the subjects, they tested a variety of fruit juices, selecting double-strength grapefruit juice prepared from frozen concentrate as most effective. 

Treatment should include correction of metabolic acidosis, inhibition of ethylene glycol metabolism and if necessary, extracorporeal elimination of the parent alcohol and metabolites. Acidemia likely increases tissue penetration of toxic metabolites and hinders renal clearance. Although evidence is lacking, bicarbonate administration should be given to correct acidemia. Although more expensive, fomepizole is preferred to ethanol for ADH inhibition due to proven efficacy, predictable pharmacokinetics, and lack of adverse effects [105]. Inhibition of ADH with fomepizole prevents formation of toxic metabolites and renal injury, and improves add-base status [106]. Elimination half-life of ethylene glycol with fomepizole in patients with preserved renal function is approximately 20 hours [107]. Pyridoxine and thiamine should be administered to promote glyoxyhc add conversion less toxic metabolites than oxalate [108]. 

There is a bioreaction engineering home problem in virtually every chapter. Bio-related web modules include physiological-based-pharmacokinetic (PBPK) models of ethanol metabolism, of drug distribution, and of venomous snake bites by the Russels viper and the cobra. 

Pharmacokinetics After ingestion, ethanol is rapidly and completely absorbed the drug is then distributed to most body tissues, and its volume of distribution is equivalent to that of total body water (0.5-0.7 L/kg). Two enzyme systems metabolize ethanol to acetaldehyde (Figure 23-1). 

Drug information resources will not provide data on the elimination half-life of ethanol because, in the case of this drug, it is not constant. The elimination of ethanol follows zero-order kinetics because the drug is metabolized at a constant rate irrespective of its concentration in the blood (see Chapter 3). The pharmacokinetic relationship between elimination half-life, volume of distribution, and clearance, given by... 

C. Pharmacokinetics. Cocaine Is well absorbed from all routes, and toxicity has been described after mucosal application as a local anesthetic. Smoking and intravenous Injection produce maximum effects within 1-2 minutes, while oral or mucosal absorption may take up to 20-30 minutes. Once absorbed, cocaine is eliminated by metabolism and hydrolysis with a half-life of about 60 minutes. In the presence of ethanol, cocaine Is transesterified to cocaethyl-ene, which has similar pharmacologic effects and a longer half-life than cocaine. (See also Table 11-59.)... 

D. Pharmacokinetics. Ethanol is readily absorbed (peak 30-120 min) and distributed into the body water (volume of distribution 0.5-0.7 L/kg or about 50 liters in the average adult). Elimination is mainly by oxidation in the liver and follows zero-order kinetics. The average adult can metabolize about 7-10 g of alcohol per hour, or about 12-25 mg/dL/h (this rate is highly variable depending on the individual). 

B. Pharmacokinetics. Ethylene glycol is well absorbed. The volume of distribution (Vd) is about 0.8 L/kg. It is not protein bound. Metabolism is by alcohol dehydrogenase with a half-life of about 3-5 hours. In the presence of ethanol or fomepizole (see below), which block ethylene glycol metabolism, elimination is entirely renal with a half-life of about 17 hours. 

B. Pharmacokinetics. Methanol is readily absorbed and quickly distributed to the body water (Vd = 0.6 L/kg). It is not protein bound. It is metabolized slowly by alcohol dehydrogenase via zero-order kinetics, at a rate about one-tenth that of ethanol. The reported half-life ranges from 2 to 24 hours, depending on whether metabolism is blocked (eg, by ethanol or fomepizole). Only about 3% is excreted unchanged by the kidneys and less than 10-20% through the breath. 

Finally, the successful application of congener analysis in casework requires considerable experience not only regarding laboratory analysis but also controlled drinking experiments. Studies of this kind furnish the information needed about the pharmacokinetics of specific congener, their interactions with ethanol metabolism and urine/blood relationships. Consequently, much basic research is necessary before embarking in actual casework, this expertise, at the present moment is available at only a few institutes of legal medicine on Germany. 

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