Ethanol elimination rates in normal and ethanol dependent animals.

Ethanol elimination rates were determined in rats using an intravenous route of ethanol administration after several experimental manipulations. Twenty-four hr food deprivation resulted in a 30% reduction to 35 mg/100ml blood/hr in elimination rate from a non-deprived rate of 50 mg/100 ml blood/hr. After 2 months of ethanol drinking (5% v/v), 24 hr starvation resulted in only a 10% reduction in elimination rate (45 mg/100 ml blood/hr), and did not increase the non-food-deprived rate (49.2 mg/100 ml blood/hr) over that obtained in the above animals' drinking water rather than 5% ethanol. Animals which chronically overdrank ethanol or water for 3 months on a schedule-induced polydipsia procedure, known to result in ethanol physical dependence, showed a decreased rate of ethanol elimination (37.9 mg/100 ml blood/hr for water drinkers) in the non-food-deprived condition. By providing 750 mg of liver powder daily as a food supplement in the ethanol overdrinking regimen, the ethanol elimination rate remained at a rate comparable to the normal animal (48.4 mg/100 ml blood/hr).     

Quantitative correlation of ethanol elimination rates in vivo with liver alcohol dehydrogenase activities in fed, fasted and food-restricted rats.

The effects of nutritional states upon liver alcohol dehydrogenase (ADH) activity and ethanol elimination rate in vivo have been examined in the rat. Male Sprague-Dawley rats, 250–280 g, were studied in the fed state, after fasting for 24, 48 and 72 hr, and after 9 days of food restriction (5g food/day). Total ADH activity per liver or per animal (2.20 m-moles/hr in fed rats) decreased after a 24-hr fast and was 1.32 and 0.94 m-moles/hr after a 48-hr fast and food restriction respectively. Cytosolic protein and liver wet weight decreased in parallel with total ADH activity, but DNA content exhibited only a 10% decrease with fasting and a 20% decrease with food restriction. Ethanol elimination rate in vivo per animal after intraperitoneal injection of 2g ethanol/kg was 1.92, 1.14 and 0.84 m-moles/hr in the fed, 48 hr-fasted and food-restricted rats, respectively. These data indicate that the decrease in the ethanol elimination rate with fasting and food restriction may be caused by decreasing ADH activity, since the cytosolic free NAD⁺/ NADH in liver after acute administration of alcohol in vivo has been reported to be nearly identical in the fed and 48 hr-fasted rats. The close agreement between liver ADH activity and ethanol elimination rate in vivo suggests that the total enzymatic activity of liver ADH is an important rate-limiting factor in ethanol metabolism under the nutritional conditions examined.     

Reproducibility of ethanol elimination rates in long-sleep and short-sleep mice

Ethanol metabolism was measured in long-sleep (LS) and short-sleep (SS) mice on two occasions separated by 1 week to test for repeatability. Mice were injected intraperitoneally with either 1.5 or 4.0 g/kg ethanol and the linear decline of blood ethanol level was measured. The parameters measured in each animal were linear ethanol elimination rate (EER), peak blood ethanol level, volume of distribution and Widmark ratio (r). Reproducibility was assessed using two statistical methods, paired t tests and Pearson correlations. Paired t tests indicated good reproducibility since the two replicate determinations did not differ significantly from each other. The other widely used indicator of reproducibility, the correlation coefficient (Pearson r) between the two measurements, was nonsignificant in almost every case, indicating poor reproducibility. This occurs because the range of values of EER is fairly narrow; thus, an individual is likely to fall anywhere within that narrow range from one day to the next, and the rank ordering of the individuals may not be maintained. Although parameters such as EER and volume of distribution appear to be reproducible for populations, they may have little or no utility as covariates in genetic analyses of individual differences in response to ethanol.     

Effect of prolonged ethanol intake on glucose metabolism in normal rats

Ingestion of an ethanol liquid diet providing 20 or 36% of daily caloric requirements for 30 days resulted in impaired responses to a glucose tolerance test and as insulin sensitivity test.     

Effect of ethanol on rates of elimination and metabolism of zoxazolamine, hexobarbital and warfarin sodium in the rat

Male rats were fed single doses of ethanol or isocaloric quantities of glucose, in solution, by stomach tube following a 6 hr fast and were injected with zoxazolamine, warfarin sodium or hexobarbital 2 or 17 hr later. Other rats were pair-fed a nutritionally adequate synthetic diet containing ethanol or isocaloric quantities of sucrose for 7–11 days, and were treated with drugs following a 17 hr fast. Plasma concentrations of each drug were determined at various intervals of time following the injections. Administration of one dose of ethanol significantly increased the rates of elimination of zoxazolamine and of hexobarbital from the circulation 17 hr later, but the rate of warfarin elimination was unchanged. Chronic ethanol feeding also increased the rate of zoxazolamine elimination; but this increase was not greater than that following acute ethanol feeding; warfarin elimination was again not altered. Rates of metabolism of the drugs by liver microsomes in vitro 17 hr after a single dose of ethanol or glucose mirrored the effects on elimination in vivo; they were significantly increased in the alcohol-treated rats in the case of zoxazolamine and hexobarbital, but not changed in the case of warfarin. The rates of elimination of zoxazolamine and warfarin from the circulation were significantly reduced in rats fed ethanol 2 hr before. It is concluded that acute ethanol intake may increase the rates of elimination of some drugs when the alcohol is no longer present, as a consequence of microsomal enzyme induction, and may decrease rates of drug elimination when alcohol is present in vivo, probably as a result of inhibition by ethanol of microsomal drug-metabolizing enzymes.     

Effect of two different types of malnutrition on the rate of elimination of ethanol in rats

Rats were fed "3% casein" or a "calorie deficient" diet, in the form of commercial pellet diet (SDS) at 50% of the amount consumed by the control group, which was fed SDS pellets ad libitum. Both of the deficient groups showed failure of weight gain in comparison with the control group. Blood levels of ethanol were measured for 3 hr after intraperitoneal injection of 1 or 1.5 g/kg at 15, 29 and 36 days after commencement of the diet. In addition the calorie deficient group was studied immediately after feeding as well as in the fasting state. Blood levels of ethanol were measured and the apparent volume of distribution and rate of removal of ethanol from the blood were calculated. A rate of ethanol metabolism/g of liver was derived. The rate of removal of ethanol was markedly decreased in the 3% casein group to less than half of control values. Three hours after injection of ethanol circulating levels were less than 50 mg/100 ml in the control and calorie deficient groups but over 200 mg/100 ml in the group fed protein deficient diets. There were no major changes in volume of distribution and the only explanation for the finding is that there is a failure of ethanol metabolism in the rats fed the low protein diet. The implication is that protein deficient human populations who often consume considerable quantities of ethanol may have a high level of tissue exposure to ethanol though the rate of metabolite formation may be low.     

Comparison of acute and chronic ethanol administration on rates of ethanol elmination in the rat in vivo

Rats were treated with ethanol employing both acute (one 6.5 g/kg dose or three 5.0 g/kg doses) and chronic (40 days treatment with the Porta diet) models. The magnitude of the increase in the rate of ethanol elimination with all three methods of treatment was similar (52–79 per cent). Furthermore, the increased rate persisted after removal of ethanol for the same time intervals irrespective of the method of treatment. The half-time of the decline was between 20 and 24 hr with all methods. The data are consistent with the hypothesis that increases in ethanol elimination due to acute as well as chronic treatment with alcohol are mediated via similar mechanisms.     

Effects of alcohol-metabolizing enzyme inhibitors and beta-lactam antibiotics on ethanol elimination in rats

The in vivo effects of alcohol-metabolizing enzyme inhibitors and beta-lactam antibiotics upon the ethanol elimination rate were examined in rats. Intravenous administration of ethanol caused a dose-dependent increase in blood ethanol level, and the ethanol elimination could be well described by a two compartment model. Pretreatment of rats with enzyme inhibitors caused a marked decrease in the ethanol elimination rate associated with the depression of the enzyme activities. Fasting of the animals caused a decrease in the ethanol elimination rate per animal associated with a decrease in the liver weight. However, no alteration was evident when the rate was expressed as the rate per g of liver. When animals were pretreated with a high dose of N-methyltetrazolethiol (NMTT)- containing beta-lactam antibiotics or NMTT itself, which causes a disulfiram-like reaction, the ethanol elimination rate per animal was depressed concomitant with an increase in the blood acetaldehyde level. The ethanol elimination rate in these animals showed lower values even when expressed as the rate per g liver. On the other hand, administration of cephems without NMTT, which cause no disulfiram-like reaction, led to a slight decline in the elimination rate per animal, although no alteration was detected when the rate was expressed as the rate per g liver. The findings indicated that the ethanol elimination in vivo per animal is regulated by the total capacity of the alcohol-metabolizing enzyme activities in the whole liver.     

The pharmacological potential of Sorbus commixta cortex on blood alcohol concentration and hepatic lipid peroxidation in acute alcohol-treated rats

The effect of Sorbus commixta cortex, a traditional herbal medicine used for the treatment of bronchitis, gastritis and dropsy, on blood alcohol concentration (BAC) and hepatic lipid peroxidation was examined in acute alcohol-treated rats. A 30-min pretreatment with a methanol extract of S. commixta cortex (SC) at concentrations higher than 200 mg kg(-1) resulted in a significant decrease in BAC and the ethyl acetate fraction (SE) of the extract showed the highest potency, with a maximum of a 46% decrease at 150 mg kg(-1) 2 h after alcohol administration (3.0 g kg(-1)) compared with the control group (P < 0.005). The rapid reduction in BAC did not appear to be due to the protection or activation of hepatic alcohol dehydrogenase (ADH) activity by SE. Hepatic malondialdehyde (MDA) levels were significantly increased by acute alcohol administration within 6 h, although pretreatment with the SE caused a significant decrease in MDA levels compared with alcohol treatment alone. Hepatic glutathione (GSH) levels and superoxide dismutase (SOD) activity remained unchanged by alcohol, SE alone or by the combined treatment of alcohol and SE. However, catalase activity was significantly reduced by acute alcohol administration and pretreatment with the SE led to significant protection of its activity. These results suggest that pretreatment with SE reduces hepatic lipid peroxidation by decreasing the bioavailability of alcohol and its oxidative metabolites, such as H2O2, at least partly, through the protection of hepatic catalase in acute alcohol-treated rats.     

Effect of sulfite on red blood cell deformability ex vivo and in normal and sulfite oxidase-deficient rats in vivo

The effect of sulfite, a widely used food additive, on red blood cell deformability ex vivo and in vivo was investigated. Ex vivo experiments were conducted in human blood exposed to sulfite (5, 10 and 20 mM). In vivo experiments were carried out in sulfite oxidase-competent (SOXC) and sulfite oxidase-deficient (SOXD) rats. In the in vivo experiments, sulfite was administered in the form of sodium metabisulfite (Na₂S₂O₅, 25 mg/kg/day) via drinking water. Vitamin E dissolved in olive oil at a dose of 50 mg/kg was administered by gastric gavages. Red blood cell (RBC) deformability was determined at various fluid shear stresses using an ektacytometer. Ex vivo sulfite exposure to RBC did not affect RBC deformability. In the in vivo experiments, although RBC deformability was not affected by sulfite treatment in SOXD rats, it was found to be significantly increased in SOXC rats. Vitamin E treatment in combination with sulfite caused impairment in RBC deformability in both SOXC and SOXD rats. We suggest that sulfite needs to be oxidized in order to improve RBC deformability.     

杨桃根醇提物对正常大鼠血压的影响

目的 研究杨桃根Averrhoa carambola root醇提物对正常大鼠血压的影响.方法 40只正常大鼠随机均分为5组:阳性对照组、正常对照组及杨桃根醇提物高、中、低剂量组.大鼠麻醉后以颈总动脉插管法连接心功能分析系统,待颈动脉血压稳定10 min后,测定给药前和十二指肠给药后30、60、90、120、150、180、210、240 min时大鼠的心率、收缩压、舒张压和平均动脉压.结果 杨桃根醇提物高剂量组大鼠的收缩压、舒张压、平均压分别于给药后60 min(由119.06±11.45 mmHg降至112.58±12.27 mmHg)、60 min(由110.91 ±9.83 mmHg降至95.44±14.82 mmHg)、90 min(由115.94±12.92 mmHg降至94.58±12.23 mmHg)开始降低;中剂量组大鼠的收缩压、舒张压、平均压分别于给药后150 min(由122.01±13.52 mmHg降至100.87 ± 15.04 mmHg)、90 min(由110.88 ± 13.75 mmHg降至89.52±17.91 mmHg)、90 min(由115.39±11.61 mmHg降至99.72±12.67 mmHg)开始降低.杨桃根醇提物对正常大鼠的心率无明显影响.结论 杨桃根醇提物能降低正常大鼠的血压.     

The roles of the hepatocellular redox state and the hepatic acetaldehyde concentration in determining the ethanol elimination rate in fasted rats

Ethanol administration (2 g/kg i.p.) to fasted male Wistar rats caused, on average, a 64% decrease in the cytosolic free NAD+:NADH ratio and a 41% decrease in the mitochondrial free NAD+:NADH ratio measured 90 min after ethanol was injected. Treatment of animals with either Naloxone (2 mg/kg i.p.) 1 hr after ethanol or 3-palmitoyl-(+)-catechin (100 mg/kg p.o. 1 hr before ethanol) prevented these ethanol induced redox state changes, without affecting the ethanol elimination rate or the hepatic acetaldehyde concentration measured at 90 min after ethanol administration. The thiol compounds cysteine and malotilate (diisopropyl-1,3-dithiol-2-ylidene malonic acid) significantly lowered the hepatic acetaldehyde concentrations measured at 0.75, 1.5 and 6.0 hr after ethanol, and caused a 29% and 12% increase respectively in the ethanol elimination rate, without affecting the ethanol induced alterations in the NAD+:NADH ratio. Pretreatment of animals with the aldehyde dehydrogenase inhibitor, cyanamide (1 mg/kg or 15 mg/kg p.o. one hour before ethanol), caused increases of up to 23-fold in the hepatic acetaldehyde level, without influencing the cytosolic NAD+:NADH ratio in ethanol dosed rats, while significantly reducing the ethanol elimination rate by up to 44%, compared with controls. These results suggest that ethanol oxidation by cytosolic alcohol dehydrogenase may be regulated in part by the hepatic acetaldehyde concentration achieved during ethanol metabolism rather than NADH reoxidation, either to supply NAD for the dehydrogenase, or to reduce inhibition of the enzyme by NADH, being a rate-limiting factor in ethanol metabolism in fasted rats.     

Behavior of blood acetaldehyde in alcohol-treated rats following administration of thiurams.

Single moderate doses of Na-dimethyldithiocarbamate and Na-diethyldithiocarbamate (thiocarb), respectively, did not influence the rate of elimination of ethanol i.p. in female rats, but there was a concurrent substantial increase in the blood acetaldehyde content. Tetramethylthiuram disulfide (thiram) produced a slight decrease in the rate of elimination of ethanol, while a comparable dose of tetramethylthiuram disulfide (disulfiram) failed to affect ethanol disappearance. At the same time, the blood acetaldehyde concentration showed a considerable increase which after thiram was much more significant than after disulfiram, Identical thiuram doses caused a significant reduction in the rate of elimination of acetaldehyde i.v., which suggests an inhibition of the aldehyde dehydrogenasel aldehyde oxidase and helps to explain the elevated blood acetaldehyde concentration which was observed in the presence of ethanol. It is concluded from these findings that thiuram activity decreases as the number of carbon atoms at the side-chains of the molecule is increasing.     

Effect of ethanol intake on disopyramide elimination by healthy volunteers

Summary The effect of ethanol intake on disopyramide elimination was examined in an open cross-over study in six healthy volunteers. No effect of ethanol on the elimination half-life or total body clearance of disopyramide was found, although it did decrease the percentage of mono-N-dealkylated disopyramide excreted in the urine (p<0.05) as well as the relative metabolic clearance of disopyramide (p<0.05). The renal clearance of disopyramide was increased by 19±16% (p<0.05) in subjects in whom ethanol caused a diuresis.     

Effect of food and food composition on alcohol elimination rates in healthy men and women.

Several studies have evaluated the effect of food on alcohol pharmacokinetics; however, most studies have used oral alcohol administration, which cannot separate the influence of food on absorption from its influence on alcohol elimination. Alcohol clamping uses intravenous alcohol and provides a direct measure of the alcohol elimination rate (AER). Two studies, using alcohol clamping at 50 mg %, were conducted to investigate the effect of food and food composition on AER (g/h) in healthymen and women. In the first study, 20 subjects underwent two clamping sessions, one after a 12-hour fast and another 1 hour after consuming a 530-calorie breakfast. In the second study, 8 subjects underwent four clamping sessions: one after a 12-hour fast and, in each of three "fed" sessions, 1 hour after a 550-calorie high-fat, high-protein, or high-carbohydrate breakfast. Comparison of AERs from the first study showed an average 25% increase following food compared to thatfollowingfasting. Men showed significantly higher AERs compared to women; however, the food effect was similar in both genders. In the second study, the AER showed a significant average 45% increase following the meal, regardless of composition, compared with that following fasting. These findings indicate that food intake results in increased alcohol elimination rates. The increase was similar for meals of different compositions, suggesting that the food effect is not due to specific interactions with meal constituents. Probable mechanisms for the increased alcohol elimination includefood-induced increases in hepatic blood flow and in the activity of alcohol-metabolizing enzymes.