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The circadian changes in elimination and absorption of amitriptyline after its intravenous and intragastric administration in rats were investigated. The values of such parameters as: AUC, MRT, t1/2, Cl, Vd, k(a) for amitriptyline change in the circadian rhythm. The fastest elimination of amitriptyline was observed in the dark phase (the acrophases for clearance were ca. 11 p.m. for iv administration and ca. 10 p.m. for po administration). The maximal value of clearance corresponds to the minimal values of MRT and t1/2. The acrophase for the constant absorption rate (po) falls at 7 p.m. Cyclic changes were not observed as far as the bioavailability is concerned.

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 different types of enzyme inducers: phenobarbital, Aroclor 1254 and benzo(a)pyrene, on distribution of amitriptyline and its metabolite nortriptyline in rats was investigated. The level of amitriptyline and nortriptyline in serum, brain, heart and liver was determined by gas chromatography. The maximum concentration values of amitriptyline and nortriptyline as well as areas under concentration-time curves (AUC0-6) in serum and organs were statistically compared using Student t test and AUCCOMP computer program. The results suggest that studied xenobiotics significantly influence the distribution of amitriptyline and nortriptyline in rats. The changes of these drugs concentration in target organs may be very important from the toxicological point of view.

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 elimination of intravenously administered theophylline was determined in rats after oral pretreatment with phenobarbital and chrysene. The pharmacokinetic parameters of theophylline (Cl, Vdss, MRT) were determined by a noncompartmental method (the moment analysis). The enzyme inducers increased the theophylline clearance from 0.157 l/kg/h in control to 0.232 l/kg/h after chrysene and 0.266 l/kg/h after phenobarbital pretreatment.

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.

The commercial mixture of pollychlorinated biphenyls (Aroclor 1254) accelerates the elimination of theophylline (given iv and po) from the body of the rat. The increase in theophylline elimination rate by Aroclor 1254 depends on Aroclor 1254 dose and time of the dosing. Aroclor pretreatment reduced the amount of orally given theophylline in that reached the circulation by 17%. This was caused by the influence of Aroclor 1254 on the elimination rate and possible first-pass effect.