Pharmacokinetics of ethanol: a review of the methodology

Abstract This paper reviews current concepts on tools for studying the pharmacokinetics of alcohol. It has been known that ethanol metabolism occurs mainly in the liver via alcohol dehydrogenase and an accessory microsomal pathway. The contribution of each pathway has been examined by administration of metabolic inhibitors. The role of gastric alcohol dehydrogenase in the first‐pass effects of ethanol has been speculative and may be relatively low. Some pharmacokinetic approaches with mathematical models have elucidated the role of gastric alcohol dehydorgenase, hepatic alcohol dehydrogenase and cytochrome P450 2E1 in ethanol elimination. The scale‐up of ethanol elimination kinetics has enabled extrapolation from animal models to human kinetics. The clarification of the pharmacokinetics of ethanol is very important for estimating the effects of ethanol on biological events.

[1]  C. Lieber,et al.  Respective roles of human cytochrome P-4502E1, 1A2, and 3A4 in the hepatic microsomal ethanol oxidizing system. , 1998, Alcoholism, clinical and experimental research.

[2]  S. Ramaswamy,et al.  Binding of formamides to liver alcohol dehydrogenase. , 1997, Biochemistry.

[3]  S. Svensson,et al.  Structural and functional divergence of class II alcohol dehydrogenase--cloning and characterisation of rabbit liver isoforms of the enzyme. , 1998, European journal of biochemistry.

[4]  J. Furne,et al.  First-pass metabolism of ethanol is negligible in rat gastric mucosa. , 1997, Alcoholism, clinical and experimental research.

[5]  M. Korsten,et al.  Metabolism of ethanol by rat pancreatic acinar cells. , 1998, The Journal of laboratory and clinical medicine.

[6]  Ting-kai Li,et al.  Gender differences in alcohol metabolism: relationship to liver volume and effect of adjusting for body mass. , 1998, Gastroenterology.

[7]  E. Laposata,et al.  Presence of nonoxidative ethanol metabolism in human organs commonly damaged by ethanol abuse. , 1986, Science.

[8]  M. Ingelman-Sundberg,et al.  Detection of cytochrome P4503A (CYP3A) in human hepatic stellate cells. , 1997, Biochemical and biophysical research communications.

[9]  J. G. Kenna,et al.  Cytochrome P450 2E1 is a cell surface autoantigen in halothane hepatitis. , 1996, Molecular pharmacology.

[10]  C. Lieber,et al.  Cytochrome P-4502E1: its physiological and pathological role. , 1997, Physiological reviews.

[11]  Ting-kai Li,et al.  Mitochondrial aldehyde dehydrogenase (ALDH2) polymorphism in AA and ANA rats: Lack of genotype and phenotype line differences , 1993, Pharmacology Biochemistry and Behavior.

[12]  E. Wang,et al.  Relationship between cytochrome P450 2E1 and acetone catabolism in rats as studied with diallyl sulfide as an inhibitor. , 1994, Biochemical pharmacology.

[13]  F. Guengerich,et al.  Differential inhibition of individual human liver cytochromes P-450 by cimetidine. , 1991, Gastroenterology.

[14]  J. F. Schindler,et al.  Inhibition of human alcohol dehydrogenases by formamides. , 1998, Journal of Medicinal Chemistry.

[15]  A W Jones,et al.  The life and work of Erik M. P. Widmark. , 1996, The American journal of forensic medicine and pathology.

[16]  D. Petersen,et al.  Ethanol elimination rates in mice: Effects of gender, nutrition, and chronic ethanol treatment , 1982, Pharmacology Biochemistry and Behavior.

[17]  M. Ingelman-Sundberg,et al.  Phenethyl isothiocyanate, a new dietary liver aldehyde dehydrogenase inhibitor. , 1995, The Journal of pharmacology and experimental therapeutics.

[18]  H. Nagasawa,et al.  Mechanisms of inhibition of aldehyde dehydrogenase by nitroxyl, the active metabolite of the alcohol deterrent agent cyanamide. , 1998, Biochemical pharmacology.

[19]  D. Scherrer,et al.  Metabolism of ethanol by human brain to fatty acid ethyl esters. , 1987, The Journal of biological chemistry.

[20]  J. Hilton,et al.  Effect of 4-(diethylamino)benzaldehyde on ethanol metabolism in mice. , 1993, Alcoholism, clinical and experimental research.

[21]  C. Lieber,et al.  High blood alcohol levels in women. The role of decreased gastric alcohol dehydrogenase activity and first-pass metabolism. , 1990, The New England journal of medicine.

[22]  Y. Fukui,et al.  Evidence that cytochrome P-4502E1 contributes to ethanol elimination at low doses: effects of diallyl sulfide and 4-methyl pyrazole on ethanol elimination in the perfused rat liver. , 1996, Alcoholism, clinical and experimental research.

[23]  M. Stebel,et al.  Influence of acid-secretion blockers on gastric and hepatic alcohol dehydrogenase in rat. , 1992, Scandinavian journal of clinical and laboratory investigation.

[24]  D. Crabb First pass metabolism of ethanol: Gastric or hepatic, mountain or molehill? , 1997, Hepatology.

[25]  U Klotz,et al.  Disposition and first‐pass metabolism of ethanol in humans: Is it gastric or hepatic and does it depend on gender? , 1996, Clinical pharmacology and therapeutics.

[26]  D. Levitt,et al.  Can the liver account for first-pass metabolism of ethanol in the rat? , 1994, The American journal of physiology.

[27]  P. Bora,et al.  Molecular mechanism of ethanol metabolism by human brain to fatty acid ethyl esters. , 1993, Alcoholism, clinical and experimental research.

[28]  D. Koop Inhibition of ethanol-inducible cytochrome P450IIE1 by 3-amino-1,2,4-triazole. , 1990, Chemical research in toxicology.

[29]  K. Lindros,et al.  No significant expression of CYP2E1 in rat liver stellate cells. , 1998, Biochemical pharmacology.

[30]  H. Seitz,et al.  Chlormethiazole inhibition of cytochrome P450 2E1 as assessed by chlorzoxazone hydroxylation in humans , 1997, Hepatology.

[31]  B. Vallee,et al.  Daidzin suppresses ethanol consumption by Syrian golden hamsters without blocking acetaldehyde metabolism. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[32]  M. Boleda,et al.  Role of extrahepatic alcohol dehydrogenase in rat ethanol metabolism. , 1989, Archives of biochemistry and biophysics.

[33]  T. Matsubara,et al.  Effects of alcohol-metabolizing enzyme inhibitors and beta-lactam antibiotics on ethanol elimination in rats. , 1987, Japanese journal of pharmacology.

[34]  B. Vallee,et al.  Daidzin inhibits mitochondrial aldehyde dehydrogenase and suppresses ethanol intake of Syrian golden hamsters. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[35]  M. Tsutsumi,et al.  Genetic polymorphisms of cytochrome P4502E1 related to the development of alcoholic liver disease. , 1994, Gastroenterology.

[36]  M. Ronis,et al.  Induction of cytochrome P450 2E1 during chronic ethanol exposure occurs via transcription of the CYP 2E1 gene when blood alcohol concentrations are high. , 1993, Biochemical and biophysical research communications.

[37]  D. Pounder,et al.  Postmortem Diffusion of Alcohol from the Stomach , 1995, The American journal of forensic medicine and pathology.

[38]  S. Sheikh,et al.  Allosteric inhibition of human liver aldehyde dehydrogenase by the isoflavone prunetin. , 1997, Biochemical pharmacology.

[39]  J. Crabbe Genetic models of alcohol dependence. , 1987, Alcohol and alcoholism (Oxford, Oxfordshire). Supplement.

[40]  C. Lieber,et al.  Ethanol Oxidation by Hepatic Microsomes: Adaptive Increase after Ethanol Feeding , 1968, Science.

[41]  K. Ameno,et al.  Inhibitory mechanism of intestinal ethanol absorption induced by high acetaldehyde concentrations: effect of intestinal blood flow and substance specificity. , 1996, Alcoholism, clinical and experimental research.

[42]  K. Kawajiri,et al.  Genetic Polymorphisms in the 5 '-Flanking Region Change Transcriptional Regulation of the Human Cytochrome P 45011 E 1 Gene ' , 2008 .

[43]  M. Lee,et al.  Modulation of rat hepatic microsomal monooxygenase enzymes and cytotoxicity by diallyl sulfide. , 1991, Toxicology and applied pharmacology.

[44]  L. Lumeng,et al.  Rat mitochondrial aldehyde dehydrogenase polymorphism and major histocompatibility complex RT1.A phenotypes are not associated with alcohol drinking in P and NP rats. , 1995, Alcoholism, clinical and experimental research.

[45]  L. J. Brunner,et al.  Gender differences in blood levels, but not brain levels, of ethanol in rats. , 1999, Alcoholism, clinical and experimental research.

[46]  A. Cederbaum,et al.  Increased sensitivity of the microsomal oxidation of ethanol to inhibition by pyrazole and 4-methylpyrazole after chronic ethanol treatment. , 1987, Biochemical pharmacology.

[47]  T. Ohshima,et al.  Experimental studies on postmortem diffusion of ethanol-d6 using rats. , 1995, Forensic science international.

[48]  D. Petersen,et al.  Inhibition of rat liver aldehyde dehydrogenases by acrolein. , 1988, Drug Metabolism And Disposition.

[49]  M. Ingelman-Sundberg,et al.  Pretranslational and posttranslational regulation of rat hepatic CYPs 3A2 and 2E1 by disulfiram. , 1997, Biochemical pharmacology.

[50]  D. Agarwal,et al.  Liver alcohol dehydrogenase and aldehyde dehydrogenase in the Japanese: isozyme variation and its possible role in alcohol intoxication. , 1980, American journal of human genetics.

[51]  Ivaylo Haratcherev,et al.  [Life and work]. , 1984, Pielegniarka i polozna.

[52]  J. Farrés,et al.  Characterization of three isoenzymes of rat alcohol dehydrogenase. Tissue distribution and physical and enzymatic properties. , 1987, European journal of biochemistry.

[53]  M. Berry,et al.  Antipyrine and aminopyrine induce acetaldehyde accumulation from ethanol in isolated hepatocytes. , 1997, Alcoholism, clinical and experimental research.

[54]  S. Imaoka,et al.  Metabolism of acetaldehyde to acetate by rat hepatic P-450s: presence of different metabolic pathway from acetaldehyde dehydrogenase system. , 1996, Alcoholism, clinical and experimental research.

[55]  S. Seki,et al.  Expression of cytochrome P450 isoforms in rat hepatic stellate cells. , 1997, Life sciences.

[56]  M. Laposata Fatty acid ethyl esters: nonoxidative metabolites of ethanol , 1998, Addiction biology.

[57]  C. Lieber,et al.  Hepatic microsomal ethanol-oxidizing system. In vitro characteristics and adaptive properties in vivo. , 1970, The Journal of biological chemistry.

[58]  B. Vallee,et al.  Daidzin: a potent, selective inhibitor of human mitochondrial aldehyde dehydrogenase. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[59]  T. Fujimiya,et al.  Role of alcohol dehydrogenase in rat ethanol elimination kinetics. , 1994, Alcohol and alcoholism (Oxford, Oxfordshire). Supplement.

[60]  Ting-kai Li,et al.  Clamping breath alcohol concentration reduces experimental variance: application to the study of acute tolerance to alcohol and alcohol elimination rate. , 1998, Alcoholism, clinical and experimental research.

[61]  M. Mayersohn,et al.  Inhibitory effect of 4-methylpyrazole on antipyrine clearance in rats. , 1992, Life sciences.

[62]  J. Russo,et al.  Identification of 4-(N,N-dipropylamino)benzaldehyde as a potent, reversible inhibitor of mouse and human class I aldehyde dehydrogenase. , 1995, Biochemical pharmacology.

[63]  T. Buclin,et al.  Inhibition of CYP2E1 by chlormethiazole as measured by chlorzoxazone pharmacokinetics in patients with alcoholism and in healthy volunteers , 1998, Clinical pharmacology and therapeutics.

[64]  M. Ingelman-Sundberg,et al.  Cytochrome P450 CYP 2E1 induction during chronic alcohol exposure occurs by a two-step mechanism associated with blood alcohol concentrations in rats. , 1993, The Journal of pharmacology and experimental therapeutics.

[65]  C. Eriksson,et al.  Voluntary Alcohol Drinking and Acetaldehyde Metabolism in F2 Hybrid Crosses of AA and ANA Rat Lines , 1997, Pharmacology Biochemistry and Behavior.

[66]  Y. Fukui,et al.  Estimation of ethanol first-pass effect in the perfused rat liver. , 1994, Alcohol and alcoholism (Oxford, Oxfordshire). Supplement.

[67]  B. Vallee,et al.  Physical and enzymatic properties of a class III isozyme of human liver alcohol dehydrogenase: chi-ADH. , 1984, Biochemistry.

[68]  R. L. Tatken,et al.  Registry of Toxic Effects of Chemical Substances , 1986 .

[69]  J. Casida,et al.  Mechanism for benomyl action as a mitochondrial aldehyde dehydrogenase inhibitor in mice. , 1998, Chemical research in toxicology.

[70]  Noncompetitive-like inhibition of ethanol elimination by cyanamide treatment: pharmacokinetic study. , 1996, Alcoholism, clinical and experimental research.

[71]  J. Bucher,et al.  Do endogenous volatile organic chemicals measured in breath reflect and maintain CYP2E1 levels in vivo? , 1997, Toxicology and applied pharmacology.

[72]  C. Lieber,et al.  Effects of ranitidine on blood alcohol levels after ethanol ingestion. Comparison with other H2-receptor antagonists. , 1992, JAMA.

[73]  M. Andersen,et al.  Gas uptake studies of deuterium isotope effects on dichloromethane metabolism in female B6C3F1 mice in vivo. , 1994, Toxicology and applied pharmacology.

[74]  H. Jörnvall,et al.  Nomenclature of alcohol dehydrogenases. , 1995, Alcohol and alcoholism.

[75]  J. Stevens,et al.  Acute effects of the aldehyde dehydrogenase inhibitors, disulfiram, pargyline and cyanamide, on circulating ketone body levels in the rat. , 1988, Biochemical pharmacology.

[76]  A. Townsend,et al.  Dependence of aldehyde dehydrogenase-mediated oxazaphosphorine resistance on soluble thiols: importance of thiol interactions with the secondary metabolite acrolein. , 1998, Biochemical pharmacology.

[77]  C. Oneta,et al.  First pass metabolism of ethanol is strikingly influenced by the speed of gastric emptying , 1998, Gut.

[78]  W. Keung,et al.  Rabbit liver alcohol dehydrogenase: isolation and characterization of class I isozymes. , 1989, Biochemical and biophysical research communications.

[79]  D. Levitt,et al.  Use of measurements of ethanol absorption from stomach and intestine to assess human ethanol metabolism. , 1997, The American journal of physiology.

[80]  C. S. Yang,et al.  Effect of phenethyl isothiocyanate on microsomal N-nitrosodimethylamine metabolism and other monooxygenase activities. , 1990, Xenobiotica; the fate of foreign compounds in biological systems.

[81]  A. Cederbaum,et al.  Oxidation of pyrazole by reconstituted systems containing cytochrome P-450 IIE1. , 1990, Biochimica et biophysica acta.

[82]  S. Milani,et al.  Human hepatic stellate cells express class I alcohol dehydrogenase and aldehyde dehydrogenase but not cytochrome P4502E1. , 1998, Journal of hepatology.

[83]  K. Reuhl,et al.  Effects of phenethyl isothiocyanate on acetaminophen metabolism and hepatotoxicity in mice. , 1997, Toxicology and applied pharmacology.

[84]  H Matsumoto,et al.  An allometric model for predicting blood ethanol elimination in mammals. , 1999, Biochemical pharmacology.

[85]  S. Nelson,et al.  Inhibition and induction of cytochrome P4502E1‐catalyzed oxidation by isoniazid in humans , 1993, Clinical pharmacology and therapeutics.

[86]  R. Thurman,et al.  Catalase-dependent ethanol metabolism in vivo in deermice lacking alcohol dehydrogenase. , 1986, Biochemical pharmacology.

[87]  K. Hatake,et al.  Liver cytosolic aldehyde dehydrogenase (ALDH1) polymorphism and its inheritance in Wistar rats. , 1997, Nihon Arukoru Yakubutsu Igakkai zasshi = Japanese journal of alcohol studies & drug dependence.

[88]  S. Imaoka,et al.  Microsomal ethanol oxidizing system activity by human hepatic cytochrome P450s. , 1995, The Journal of pharmacology and experimental therapeutics.

[89]  Y. Fukui,et al.  Mitochondrial ALDH polymorphism affects ethanol-derived acetate disposition in Wistar rats. , 1996, Alcoholism, clinical and experimental research.

[90]  D. Levitt,et al.  Use of a two-compartment model to assess the pharmacokinetics of human ethanol metabolism. , 1998, Alcoholism, clinical and experimental research.

[91]  D. Crabb,et al.  Detection of a CA repeat polymorphism in the rat class I alcohol dehydrogenase gene. , 1993, Alcoholism, clinical and experimental research.

[92]  D. Keilin,et al.  Properties of catalase. Catalysis of coupled oxidation of alcohols. , 1945, The Biochemical journal.

[93]  C. Lieber,et al.  First pass metabolism of ethanol--a gastrointestinal barrier against the systemic toxicity of ethanol. , 1985, Life sciences.

[94]  J. R. Wilson,et al.  Ethanol metabolism in men and women. , 1987, Journal of studies on alcohol.

[95]  L. Lumeng,et al.  Polymorphism of the rat liver mitochondrial aldehyde dehydrogenase cDNA. , 1991, Alcoholism, clinical and experimental research.

[96]  A. Jones,et al.  Influence of age, gender, and blood-alcohol concentration on the disappearance rate of alcohol from blood in drinking drivers. , 1996, Journal of forensic sciences.

[97]  T. Fujimiya,et al.  Parallel first-order and Michaelis-Menten elimination kinetics of ethanol. Respective role of alcohol dehydrogenase (ADH), non-ADH and first-order pathways. , 1989, The Journal of pharmacology and experimental therapeutics.

[98]  N. D. Kim,et al.  Inhibition of cytochrome P450 2E1 expression by 2-(allylthio)pyrazine, a potential chemoprotective agent: hepatoprotective effects. , 1997, Biochemical pharmacology.

[99]  P. Thomas,et al.  Effects of phenethyl isothiocyanate, a carcinogenesis inhibitor, on xenobiotic-metabolizing enzymes and nitrosamine metabolism in rats. , 1992, Carcinogenesis.

[100]  B. Vallee,et al.  New human liver alcohol dehydrogenase forms with unique kinetic characteristics. , 1981, Biochemical and biophysical research communications.

[101]  M. Ingelman-Sundberg,et al.  Zonated expression of cytokines in rat liver: Effect of chronic ethanol and the cytochrome P450 2E1 inhibitor, chlormethiazole , 1998, Hepatology.