Pharmacokinetics of ethanol

The rate-limiting factor in the metabolism of ethanol is the availability of NAD.  

Ethanol is not metabolized by cytochrome P-450 enzymes (microsomal drug-metabolizing systems, or MEDS). However, it is metabolized to a certain extent by the microsomal ethanol-oxidizing system (MEOS). 

Although ethanol is not metabolized by the microsomal drug-metabolizing system, it inhibits it and increases the rate of its synthesis. This effect may create a significant alcohol-drug interaction in both nonalcoholics and alcoholics who are taking medications. 

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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],... 

Robinson DL, Brunner LJ, Gonzales RA. 2002. Effect of gender and estrous cycle on the pharmacokinetics of ethanol in the rat brain. Alcohol Clin Exp Res 26(2) 165-172. 

Jones AW. Pharmacokinetics of ethanol in saliva comparison with blood and breath alcohol profiles, subjective feelings of intoxication, and diminished performance. Clin Chem 1993 39 1837-44. 

Giire C, Coutelle C, David P, Fleury B, Thomas G, Palmobo S, Dally S, Couzigou P. Lack of effect of lansoprazole on the pharmacokinetics of ethanol in male volunteers. Gastroenterology (1994)106, A504. 

Jonsson K-A, Jones AW, Bostrom H, Andersson T. Lack of effect of omeprazole, cimetidine, and ranitidine on the pharmacokinetics of ethanol in fasting male volunteers. EurJ Clin Pharmacol ( 992) 42, 209-212. 

Kechagias S, Jonsson K-A, Jones AW. Impact of gastric emptying on the pharmacokinetics of ethanol as influenced by cisapride. BrJClin Pharmacol (1999) 48, 728-32. 

Drug-drug interactions Simultaneous use of ethanol and retigabine leads to elevated levels of retigabine, with no impact on the pharmacokinetics of ethanol. No clinical effects were observed other than those attributable to ethanol use alone [154 ]. 

P. K. Wilkinson, et al "Pharmacokinetics of Ethanol After Oral Administration in the Fasting State J. Pharmacoket. Biopharm.. 5(3) 207-24 (1977). 

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). 

Kaneko T, Wang P-Y, Sato A. 1994. Enzymes induced by ethanol differently affect the pharmacokinetics of trichloroethylene and 1,1,1-trichloroethane. Occup Environ Med 51 113-119. 

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]. 

Animal studies Pharmacokinetics of hyperforin after administration of an ethanolic SJW extract (WS 5572, Dr. Willmar Schwabe, Karlsruhe, Germany) to rats were investigated by Biber et al. (72). Maximum plasma levels of approximately 370ng/mL (approximately 690 nM) were reached after three hours. Estimated half-life and clearance values were six hours and 70mL/min/kg, respectively. 

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. 

To date, only one study has evaluated the pharmacokinetics of the alkamides contained in the Echinacea products administered to humans (27). Subjects (n - 11) received a single oral 2.5-mL dose of the 60% ethanolic extract from E. angustifolia roots or placebo (60% ethanol). Six different alkamides were analyzed (1) Undeca-2D/Z-ene-8,10-diynoic acid isobutylamides (2) Dodeca-2D,4Z-diene-8,10-diynoic acidisobutylamide (3) Dodeca-2E-ene-8,10-diynoic acid isobutylamide (4) Dodeca-2E,4E,8Z,10E/ Z-tetraenoic acid isobutylamides (5) Dodeca-2E,4E,8Z-trienoic acid isobutylamide and (6) Dodeca-2E,4E-dienoic acid isobutylamide. The extract contained approx 2.5 mg of (4), and approx 0.5 mg of all other components. The Cmax and area under the curve (AUC) for (4) were approx 10-fold that achieved with each of the other components. Thus, despite a fivefold higher amount per dose, the 10-fold greater Cmax and AUC achieved with (4) suggest it exhibits a greater bioavailability than the other components. 

A mixture of ethanol (12.8%), PEG, cremophor EL, Tween 80, propylene glycol, and sorhitan monooleate solubilizes 25 or 100 mg of Cyclosporin A in Gengraf hard gelatin capsules. Gengraf and Neoral are bioequivalent with virtually identical pharmacokinetics. 

Data describing the interaction of 2-butoxyethanol or 2-butoxyethanol acetate with other chemicals are scarce. Simulations of human pharmacokinetics of co-exposure to ethanol (0.1% in the blood) during an 8-hour exposure to 20 ppm 2-butoxyethanol with no exercise predict that the arterial levels of 2-butoxyethanol will be elevated as a result of a decrease in elimination rate (Johanson 1986, 1991a Johanson and Naslund 1988). Because the increase in 2-butoxyethanol is due to decreased elimination and not increased uptake, the rise and fall of blood concentrations of 2-butoxyethanol are slower in the ethanol co-administration model than in the increased workload model. A study in rats indicated that co-administration of ethanol and 2-butoxyethanol resulted in a higher blood level and a prolonged blood... 

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. 

Describe the pharmacodynamics and pharmacokinetics of acute ethanol ingestion. 

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.)... 

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. 

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