The kinetics of ethanol absorption and elimination in twins and supplementary repetitive experiments in singleton subjects

Kopun, Marijana; Propping, Peter

doi:10.1007/bf00566530

Cited by 134 publications

(42 citation statements)

References 16 publications

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“…The Widmark B60 (sometimes erroneously shortened to B) has been the classical parameter used to describe ethanol elimination rated and reported values (Kopun & Propping, 1977) are identical to the rate of 0.11 g h-' kg-' calculated in our study. Comparatively the more rational Michaelis-Menten rate, Vmax is remarkably similar at 0.…”

Section: Resultssupporting

confidence: 83%

“…This view has been perpetuated by many investigators with the use of arithmetic linear regression techniques and Widmark's coefficients (Kopun & Propping, 1977;Newman, Lehman & Cutting, 1937;Vesell, Page & Passananti, 1971). Haggard & Greenberg (1934) first suggested concentrationdependent elimination rates for ethanol and Lundquist & Wolthers (1958) showed that the Michaelis constant derived from experiments in man closely approximated that for alcohol dehydrogenase (ADH) in vitro.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ethanol ‘dose‐dependent’ elimination: Michaelis‐Menten v classical kinetic analysis.

Re¹,

Kreeft²,

Sitar³

1981

Brit J Clinical Pharma

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Section: Resultssupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Ethanol ‘dose‐dependent’ elimination: Michaelis‐Menten v classical kinetic analysis.

Re¹,

Kreeft²,

Sitar³

1981

Brit J Clinical Pharma

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“…In humans, smokers have faster alcohol metabolism than nonsmokers (Kopun and Propping, 1977;Morabia et al, 1999), and smoking increases alcohol consumption (Barrett et al, 2006). In rats, nicotine increases ethanol consumption and can result in reinstatement of alcohol-seeking behavior (Le et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

In Vivo and in Vitro Characterization of Chlorzoxazone Metabolism and Hepatic CYP2E1 Levels in African Green Monkeys: Induction by Chronic Nicotine Treatment

Lee¹,

Yue²,

Tyndale³

2006

Drug Metab Dispos

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ABSTRACT:CYP2E1 metabolizes compounds, including clinical drugs, organic solvents, and tobacco-specific carcinogens. Chlorzoxazone (CZN) is a probe drug used to phenotype for CYP2E1 activity. Smokers have increased CZN clearance during smoking compared with nonsmoking periods; however, it is unclear which cigarette smoke component is causing the increased activity. The relationships between in vivo CZN disposition, in vitro CZN metabolism, and hepatic CYP2E1 have not been investigated in a within-animal design. In control-treated monkeys (Cercopithecus aethiops), the in vivo CZN area under the curve extrapolated to infinity (AUC inf ) was 19.7 ؎ 4.5 g ؋ h/ml, t 1/2 was 0.57 ؎ 0.07 h, and terminal disposition rate constant calculated from last three to four points on the log-linear end of the concentration versus time curve was 1.2 ؎ 0.2 /h. In vitro, the apparent V max was 3.48 ؎ 0.02 pmol/ min/g microsomal protein, and the K m was 95.4 ؎ 1.8 M. CYP2E1 is a drug-metabolizing enzyme that biotransforms many compounds, including clinical drugs such as acetaminophen and halothane (Caro and Cederbaum, 2004). CYP2E1 also metabolizes ethanol (Lieber, 1999) and can be induced by ethanol in rats (Howard et al., 2001), rabbits (Lieber, 1999), and humans (Oneta et al., 2002). CYP2E1 contributes to ethanol metabolism at high blood alcohol concentrations in humans (Salaspuro and Lieber, 1978) and rats (Matsumoto et al., 1996). Many low molecular weight compounds such as benzene and carbon tetrachloride are also CYP2E1 substrates (Caro and Cederbaum, 2004). CYP2E1 produces a high level of reactive oxygen species, without need of a ligand, that can result in cell damage from lipid peroxidation and DNA strand breaks (Caro and Cederbaum, 2004).Chlorzoxazone (CZN), a clinically used muscle relaxant, is metabolized by CYP2E1 to 6-hydroxychlorzoxazone (6OHCZN), and this reaction has been established as a phenotypic measure of CYP2E1 activity in vivo in humans (Lucas et al., 1999) and in vitro in rats (Kobayashi et al., 2002) and cynomolgus monkeys (Amato et al., 1998). No studies linking in vivo CZN disposition, in vitro hepatic CZN metabolism, and hepatic CYP2E1 protein levels have been published in any species. The in vivo CZN disposition, in vitro CZN metabolism, and hepatic CYP2E1 protein levels have not yet been investigated in African green monkeys (vervets, Cercopithecus aethiops). This monkey is a useful model of human metabolism; it has been established as a model of CYP2A6 (Schoedel et al., 2003) and CYP2B6 (Lee et al., 2006) isozyme metabolism. Our model provides an opportunity to investigate the relationship between these three variables in a nonhuman primate. African green monkey CYP2E1 has not yet been sequenced, but it is expected to have similar amino acid homology to that of human CYP2E1. Other monkeys such as the cynomolgus monkey (Macaca fascicularis) and the rhesus monkey (Macaca mulatta) have 92 and 95% amino acid homology to human Conflict of Interest Statement: R.F.T. is a shareholder in Nicogen, a company fo...

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“…Ethanol metabolism and elimination have been reported to range from 58 to 148 mg/kg/hr (Kopun and Propping, 1977), or 4 to 11 g/hr in a 70 kg man, with more rapid metabolism and elimination of ethanol noted in heavy drinkers (Jones, 1993) and chronic alcoholics (Nuutinen et al, 1985). Thus, the quantity of alcohol present in three standard drinks (one standard drink is considered equivalent to 13.6 g absolute ethanol; Sobell and Sobel, 1992) can be metabolized in 4 to 6 hr in an average male drinker.…”

Section: Discussionmentioning

confidence: 99%

Platelet Adenylyl Cyclase Activity as a Trait Marker of Alcohol Dependence

Menninger

Barón

Conigrave

et al. 2000

Alcoholism Clin & Exp Res

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Background: There is compelling evidence that genetic factors play a major role in the development of alcohol dependence. Platelet adenylyl cyclase (AC) activity has been proposed as a biochemical marker for differentiating alcohol-dependent and nondependent subjects, but the sensitivity and specificity of this marker have not been ascertained. The objective of this study was to determine the sensitivity and specificity of platelet AC activity in identifying alcohol-dependent subjects and to ascertain the effect of medical/ psychiatric variables, drinking and smoking history, and age and body weight on AC activity.Methods: The cross-sectional study was conducted from 1995 to 1998. Participants were 210 Australian White men who were community volunteers and alcohol treatment inpatients in Sydney, Australia. There were 41 nondrinkers, 140 drinkers, and 29 men who were entering alcohol treatment. The main outcome measure was platelet AC activity. Classification variables were plasma ethanol, ␥-glutamyltransferase, aspartate aminotransferase, serum carbohydrate-deficient transferrin (CDT), and urinary 5-hydroxytryptophol/5-hydroxyindoleacetic acid (5-HTOL/5-HIAA) levels, and World Health Organization/International Society for Biomedical Research on Alcoholism Interview Schedule variables, which included alcohol use and dependence criteria.Results: Among subjects who reported abstinence for at least 4 days, both cesium fluoride (CsF)-and forskolin-stimulated platelet AC activities were significantly lower in those with a lifetime history of alcohol dependence compared with those with no such history (p Ͻ 0.005 and p Ͻ 0.05, respectively). The sensitivity and specificity of CsF-stimulated AC activity to discriminate individuals with a lifetime history of alcohol dependence were 75% and 79%, respectively. Similar values for sensitivity and specificity for CsFstimulated AC activity were calculated when discriminating current alcohol dependence in the subjects in our sample. Irrespective of the history of alcohol dependence, persons who had consumed alcohol recently (within the last 3-4 days) showed significantly higher mean basal, CsF-stimulated, and forskolin-stimulated AC activity (p Ͻ 0.001), as did those who had elevated 5-HTOL/5-HIAA ratios or CDT levels, indicative of recent (heavy) drinking. The "normalization" of platelet AC activity to baseline levels after an individual stops drinking may be related to the generation of new platelets during the abstinence period. Conduct disorder and antisocial personality disorder were not associated with low AC activity, but low forskolinstimulated AC activity was associated with major depression.Conclusions: We found that CsF-and forskolin-stimulated platelet AC activity discriminates between subjects with and without alcohol dependence in a population of subjects who had not consumed significant quantities of ethanol recently. Recent alcohol consumption is a confounding variable that can alter the measured levels of AC activity. Forskolin-stimulated platelet AC activity al...

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The kinetics of ethanol absorption and elimination in twins and supplementary repetitive experiments in singleton subjects

Cited by 134 publications

References 16 publications

Ethanol ‘dose‐dependent’ elimination: Michaelis‐Menten v classical kinetic analysis.

Ethanol ‘dose‐dependent’ elimination: Michaelis‐Menten v classical kinetic analysis.

In Vivo and in Vitro Characterization of Chlorzoxazone Metabolism and Hepatic CYP2E1 Levels in African Green Monkeys: Induction by Chronic Nicotine Treatment

Platelet Adenylyl Cyclase Activity as a Trait Marker of Alcohol Dependence

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