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Background: A vast majority of people who abuse alcohol are also defined as "heavy smokers". Tobacco smokes induces CYP1A1, CYP1A2, CYP2A6 isoenzymes, but on the other hand, ethanol activates CYP2E1, which can be important during combined, chronic use of both of them. The aim of the study was to evaluate the influence of tobacco smoke xenobiotics on ethanol pharmacokinetics and the level of its metabolites in alcohol preferring and non-preferring rats., Methods: Ethanol, acetaldehyde, methanol, n-propanol and n-butanol were determined in whole blood by means of gas chromatography. Cotinine in serum was determined by LC-MS/MS. A non-compartmental analysis (cotinine, acetaldehyde) and Widmark equation (ethanol) were used for pharmacokinetic parameters calculation., Results: Ethanol levels were lower in animals exposed to tobacco smoke compared to rats receiving this xenobiotic, without a prior exposure to tobacco smoke. Lower values of the studied pharmacokinetic parameters were observed in the alcohol preferring males compared to the non-alcohol preferring rats. Both n-propanol and n-butanol had higher values of the pharmacokinetic parameters analyzed in the animals exposed to tobacco smoke and ethanol compared to those, which ethanol was administered only once., Conclusions: An increase in maximum concentration and the area under concentration-time curve for ethanol after its administration to rats preferring alcohol and exposed to tobacco smoke are accompanied by a decrease in the volume of distribution. The changes in the volume of distribution may be caused by an increase in the first-pass effect, in the intestinal tract and/or in the liver. The acetaldehyde elimination rate constant was significantly higher in alcohol-preferring animals., (Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Background: Tobacco smoking and alcohol abuse causes oxidative stress in humans and underlay numerous chronic degenerative diseases. Liver is the main organ exposed to alcohol toxic metabolites, whereas tobacco smoke is chiefly harmful to the lungs., Methods: The aim of the current study was the assessment and comparison of selected oxidative stress markers, reduced glutatione (GSH), glutathione S-transferase (GST), superoxide dismutase (SOD), catalase, nitrites and protein nitrosylation and DNA damage in the livers and in the lungs of alcohol-addicted rats exposed to tobacco smoke alone or in combination with a single dose of ethanol., Results: The highest levels of GSH were measured in the liver of smoke only exposed animals and in the lungs of rats exposed to smoke and alcohol. In the liver of animals treated with a single dose of alcohol or with smoke and alcohol, GST was significantly higher than in the group exposed to smoke only. SOD and catalase showed the highest activities in the livers of rats receiving a single dose of alcohol. High concentration of nitrites was observed in the lungs of animals treated with smoke and alcohol in combination, which corresponded to elevated protein nitrosylation in this group, whereas in the livers of these animals relatively low level of nitrites was accompanied with the lowest concentration of nitrosylated proteins. In the liver of alcohol only treated rats the highest nitrites corresponded to the highest protein nitrosylation. In the lungs of all treatment groups the range of DNA damage was higher, than the respective values in the livers. Although alcohol is not considered a specific toxicant to the lungs it was found to cause oxidative stress in this organ., Conclusions: The obtained results suggest that in the ethanol-addicted rats combined exposure to smoke and alcohol differentially modulate endogenous antioxidant defense system and reactions to oxidative stress.

Background: Previous results proved that simultaneous effect of tobacco smoke constituents and alcohol consumption may change toxicity of these substances and have a greater effect on hepatic and pancreatic disease and cancer risk. The aim of this study was to investigate hepatocyte and pancreatic cells regeneration after tobacco and/or ethanol treatment., Methods: In the study, four groups of rats were used - alcohol non-addicted and addicted male and female rats. The animals from each group were exposed to tobacco smoke, to ethanol or tobacco smoke and ethanol. After the exposure, pancreas and liver were collected at two time-points--5 and 24 h. Biochemical methods were used to measure concentration of ethanol and cotinine in blood and plasma. Additionally, proliferating cell nuclear antigen labeling index (PCNA-LI), an S-phase marker was assessed by immunohistochemical staining and morphometric method., Results: Our experimental results showed that the exposure of rats to tobacco smoke does not have influence on ethanol concentration in blood of non-addicted (male, female) and addicted (male and female) animals. The results also proved that alcohol addiction did not influence nicotine metabolism in all animals exposed to tobacco smoke. Morphological studies of tissues display significant damage in liver of addicted males, including fatty degradation, fibrosis and slight inflammatory infiltrate. Immunohistochemical studies revealed at first, significant increase of PCNA-LI and, thus, increased cell proliferation activity and damage in tissues were observed in hepatic and pancreatic cells of addicted males when compared with non-addicted males. Secondly, comparison between addicted males and addicted females revealed that PCNA-LI in females is significantly lower, both in hepatic and pancreatic tissues. And finally, animals exposed only to ethanol and to tobacco smoke plus ethanol were characterized by higher percentage of PCNA positive cells in relation to animals exposed only to tobacco smoke., Conclusion: From the preliminary study one can conclude that the influence of ethanol and simultaneous influence of ethanol and tobacco smoke impairs liver and pancreatic functions to a greater degree than tobacco abuse.

Usually, alcohol addicted persons smokes cigarettes. In the study, the effect of combined exposure to alcohol and tobacco smoke in alcohol addicted rats on liver peroxidation was evaluated. Alcohol abuse and its presence in blood did not influence the cotinine level, what indicates the lack of the importance of this factor in nicotine metabolism. Similarly, enzymatic markers of liver damage (AspAT, AIAT, ALP) did not change, what showed lack of hepatotoxic effect studied compounds in applied model of alcohol addiction and tobacco smoke exposure. Combined exposure to alcohol and tobacco smoke increases the level of lipid peroxidation in brain, liver and lungs however decreases in serum. In kidneys the results are not unambiguous.

This study aimed to evaluate the impact of nicotine and other xenobiotics contained in tobacco smoke on the pharmacokinetics of ethyl alcohol and on the levels of toxic ethanol metabolites such as acetic aldehyde.We also sought to evaluate the impact of a one-time administration of ethyl alcohol on the biotransformation of nicotine, the addictive alkaloid of tobacco smoke, to its main metabolite, cotinine. Rats were divided in three groups. The first group was exposed to tobacco smoke (6 h per day, for 5 days), the second group was treated with alcohol (2 g/kg), and the third group was exposed to tobacco smoke and treated with alcohol. Earlier exposure to tobacco smoke had an insignificant impact on the elimination of alcohol, but caused a significant increase in the volume of distribution, which could be caused by an increase in the first-pass effect. In contrast, inhaling tobacco smoke decreased acetic aldehyde concentrations in the first hour after alcohol administration. The major finding of this study was that a single dose of ethyl alcohol increases the rate of elimination of cotinine, the major metabolite of nicotine. This was demonstrated by a reduced biological half-life (t(0.5)) and mean resident time (MRT).

Ethanol is oxidized to acetaldehyde by alcohol dehydrogenase (ADH) and this is the main way of alcohol oxidizing in social drinkers. Microsomal Ethanol Oxidizing System (MEOS) is induced in ethanol addicted individuals and plays the main role in ethanol oxidation in this group. The aldehyde dehydrogenase (AIDH), enzyme oxidizing acetaldehyde to acetic acid, activity is not induced and does not get changed. This may lead to acetaldehyde cumulation in alcoholics. The aim of the study was to define the usefulness of acetaldehyde concentration measurement in the blood as the marker of alcohol addiction. 53 alcohol addicted and acutely poisoned patients (males) participated in the study. The control group was social drinkers, 43 males, accidentally poisoned with ethanol. Alcohol addiction was diagnosed according to ICD-10 criteria. Ethanol and acetaldehyde measurements were carry out on admission. The ethanol concentration in blood was measured by enzymatic method (ADH) and acetaldehyde concentration using headspace gas chromatography. Because of differences of ethanol concentrations in two examined groups (alcoholics and social drinkers) the normalization of acetaldehyde results was performed dividing acetaldehyde concentration by ethanol concentration. The results indicated higher blood acetaldehyde and ethanol concentrations in alcoholic individuals acutely poisoned with ethanol in comparison to acutely poisoned social drinkers. The acetaldehyde/ethanol ratio, used in the study, is higher in alcoholics as well and the difference is statistically significant. These results suggest the usefulness of acetaldehyde concentration measurement as a marker of ethanol addiction.

Basing on toxicological examination performed between December 1, 2001 and November 6, 2002 the analysis of cardiotoxic agents was carried out. As much as 69.7% of 2523 positive results was related to cardiotoxic agents. Ethanol (57.4%) followed by anticholinergic drugs (15.7%), amphetamine (11.6%) and carbon monoxide (8.9%) were most frequently determined cardiotoxic agents. Relatively small number of cardiovascular medication drugs (0.3%) was stated in biological samples. The cardiotoxic agents were detected mostly in men (68.8%), even after ethanol was excluded from the analysis (54.8%).

The presence of volatile compounds, such as acetone, acetaldehyde, methanol, ethanol, isopropanol, and n-propanol, in the blood of 169 acutely poisoned alcoholics was determined. The clinical diagnosis of addiction was made on the basis of a patient interview as well as physical, psychological, and psychiatric examination. At the time of the patients' admission to the clinic, the mean concentration of ethanol in blood was 3.14 +/- 1.10 g/l and its elimination rate in the studied group was 0.27 +/- 0.08 g/kg/hr, an elimination rate significantly higher (P <.001) than that of social drinkers, which averages to 0.014 +/- 0.04 g/kg/h. The presence of other volatile compounds in the blood of alcohol-addicted patients is common. The calculated elimination rate constant of methanol was about 0.2 h(-1). This rate seems to indicate that, in heavy drinkers, the elimination of methanol may be relatively fast even if the ethanol concentration is above 1 g/l. The elimination of other volatile compounds can be accelerated by large doses of ethanol, although it is not correlated with actual blood ethanol level. Moreover, in most of the blood samples with a methanol concentration below 10 mg/l, the measured concentration of acetone was below 7 mg/l and that of isopropanol was below 2 mg/l.

In most research, the inter- and intra-individual variability of time profiles of ethanol concentration has been studied over a relatively short period of time. We present a study of inter- and intra-individual variability of ethanol pharmacokinetics in five healthy volunteers (social drinkers) over a period of around eight years. The volunteers received a dose of 0.7 g/kg (men) and 0.6 g/kg (women) of ethanol in the form of vodka diluted with mineral water. The blood ethanol concentrations in a series of samples were measured by gas chromatography. For pharmacokinetic calculations, a model with first-order absorption and Michaelis-Menten elimination was applied. A linear regression technique was used to calculate Widmark's coefficient. The area under the concentration-time curve (AUC) was calculated by trapezoid rule. A tendency for pharmacokinetic parameters to alter during the study time was observed, however, these changes were random and did not correlate with the duration of the study. The highest inter- and intra-subject variability of the half time of absorption was observed. The maximal elimination velocity and Michaelis-Menten constant were also very unstable; coefficients of variation were 55.8% and 79.0%, respectively. Other calculated pharmacokinetic parameters (AUC, beta60, V/F, Cmax) were characterized by a lower variability with a coefficient of variation around 36%. Back extrapolation of plasma ethanol concentration using mean value of beta60 for each subject showed that results could be underestimated up to 26% or overestimated up to 102%.

Circadian changes in the elimination of ethanol after its administration in the rats in two doses: low (1.5 g/kg) and high (4.5 g/kg) were investigated. Circadian rhythm in ethanol pharmacokinetics (AUC, CLpo, t1/2) was observed after the low dose but not after the high one. The maximum rate of elimination was in the dark (active) phase at 1 am. The maximum value of clearance was related to the minimum value of AUC. Although the maximum and the minimum values of Vmax and KM differed essentially the diurnal variation were not observed.

The aim of this work was to determine the influence of ethanol on the antiarrhythmic activity of verapamil in the model of calcium arrhythmia in rats non-dependent and dependent on ethanol. The results of the experiment show that a combined, single administration of ethanol and verapamil attenuates in a statistically significant manner the antiarrhythmic effect of verapamil. Ethanol administered repeatedly together with verapamil does not diminish the antiarrhythmic activity of verapamil.

The antiarrhythmic action of diltiazem in the model of barium arrhythmia was studied in rats non-dependent and dependent on ethanol. The results of our studies showed that single intragastric administration of ethanol jointly with diltiazem did not significantly attenuate the antiarrhythmic effect of diltiazem. Ethanol administered repeatedly and jointly with diltiazem influenced the antiarrhythmic action of diltiazem in different ways, depending on the used dose of diltiazem. After repeated joint administration of ethanol and diltiazem in a lower dose, attenuation of the antiarrhythmic effect of diltiazem was not observed. Repeated joint administration of ethanol and diltiazem in a higher dose attenuated the antiarrhythmic effect of diltiazem. Those experiments also showed that single administration of diltiazem did not significantly influence the ethanol level in the blood; however, when administered repeatedly, diltiazem reduced the concentration of ethanol in blood.

The influence of ethanol in single and multiple doses on concentration-time profile of amitriptyline (1) and nortriptyline (2) in rat serum, brain, heart, and liver was studied. AUC0-6 values were calculated and statistically compared as well as cmax values in serum and tissues. Ethanol inhibited N-demethylation of 1 and therefore 2 has not been detected in biological material. AUC0-6 and cmax values were less than in control group. All AUC0-6 and cmax values for 1 in ethanol treated groups of rats were statistically significant compared with the control group.

The effect of ethyl alcohol on the antiarrhythmic action of atenolol in the adrenaline-induced arrhythmia model was studied in rats non-dependent and dependent on ethanol. Atenolol administered jointly with ethanol, in a single dose or repeatedly produced a weaker antiarrhythmic effect than when it was given alone. Moreover, a rise in animal mortality was observed, in particular after atenolol administration in the period of intoxication. No significant effect of atenolol on ethanol blood concentration was found.

The antiarrhythmic activity of amiodarone was studied in the model of adrenaline-induced arrhythmia in rats non-dependent and dependent on ethanol. After single or repeated joint administration of ethanol and amiodarone the antiarrhythmic effect of amiodarone was attenuated. No significant differences in the activity of amiodarone were observed when the drug was administered in the period of abstinence.