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In a group of 112 patients aged 65 to 72 years with chronic gastritis (48 persons), a peptic ulcer (30 persons), a duodenal ulcer (34 persons) bacteriological examinations were conducted aiming at determining the sensitivity to antibiotics of Helicobacter pylori (H. pylori) strains isolated from the month (gingival pockets), the stomach or duodenal mucous, from stool samples and from the skin of the hands. The sensitivity to antibiotics was tested with the diffusive-disc method taking into consideration 23 chemotherapeutic agents. It was shown that with the use of single antibiotics the chance of efficiently elimination the H. pylori infection from the area of the whole alimentary canal (month, stomach, duodenum, large bowel) amounted to 14.3-35.7% depending on the chemotherapeutics used, where with the use of a two-medicine therapy (metronidazol + amoxycillin) it increased to 42.9%. This means that in people of an advanced age the chemotherapy carried out with the aim of liquidating the infection in the stomach or duodenum mucousa creates possibilities for the H. pylori infection to persist in other parts of the alimentary canal ranging from 64.3 to 85.7%. This way the patient treated may then undergo self-infection as well as be a source of infection for other persons.

Hair analysis offers the possibility of revealing an individual's recent history of drug exposure beginning at sampling day and dating back over a period of weeks or months. This feature of hair analysis can be applied in clinical setting for monitoring drug use by addicted patients being rehabilitated. The aim of this study was to apply determination of major opiates and amphetamines in hair to confirm medical interview made by a physician in detoxification and methadone treatment patients. These assays used gas chromatography coupled to mass spectrometry (GC/MS) for opiates and liquid chromatography coupled to atmospheric pressure chemical ionisation mass spectrometry (LC/MS-APCI) for amphetamines. Most unconfirmed interview data were in the group of detoxification patients. Four methadone patients were negative for opiates.

The exposition to tobacco smoke is overall: in home, work and public places. For the examination of the presence and concentration of environmental tobacco smoke (ETS) in indoor environments the nicotine and respirable suspended particulates (RSP) are determined. A variety of biomarkers (nicotine, cotinine, thiocyanate, carboxyhemoglobin, protein and DNA adducts) are propose for measurement of exposure to tobacco smoke. The most popular is measurement of cotinine concentration in body fluids (blood, urine, saliva). Plasma cotinine concentration correlated to numbers of cigarettes smoked and to various biological effects of cigarette smoking and exposure to ETS. Other biomarkers as carboxyhemoglobin, thiocyanate, and amines and polycyclic aromatic hydrocarbons adduct can be also use.

The study included 61 patients (35 men and 26 women) ages 47 to 74 in whom a primary liver cancer was diagnosed or neoplastic metastases to the liver were confirmed in the course of a cancer of the stomach or the large bowel. In each patient the endogenous serum diazepam concentration (ESDC) was estimated chromatographically and the results obtained were compared to selected clinical traits such as the magnitude and number of neoplastic changes and their location in the liver parenchyma, the histological form of the tumor and the primary location of the cancer in the case of neoplasms of the alimentary canal. The determination of the ESDC was also carried out in a control group made up of voluntary blood donors. Neither group examined received any medication belonging to the benzodiazepine group. From the results of the tests conducted it was confirmed that the average ESDC of patients with liver neoplasms was 65 times higher than that of the control group. Simultaneously, however, in patients with a primary liver cancer the average endogenous concentration was higher than in patients with neoplastic metastases to that organ and this was statistically significant. The location in the hepatic parenchyma of the neoplastic change as well as the primary location of the cancer remained without a statistically significant influence in the changes of ESDC. It was moreover shown that significantly high ESDC were associated in the liver mainly with increased neoplastic growth (above 3 cm in diameter) and with multiple spread (5 focuses and more).

The studies included 170 patients (103 men and 67 women) aged 23 to 66 years, operated on because of an ulcerous disease. Depending on the method of surgical treatment patients were divided into 5 groups (those after gastric resection with Rydygier's method, after resection with the Billroth II method, after trunk vagotomy with pyloroplasty, after highly selective vagotomy, and after gastro-enterostomy). In all patients a qualitative estimation of the nitrate-reducing bacteria was carried out, as well as a chromatographic test of the selected N-nitrosamine concentration in the gastric juice. It was shown that the changes in the quantity of the nitrate-reducing bacteria and in the N-nitrosamine concentration depended on the type of surgical intervention conducted. The largest mean content of nitrate-reducing bacteria and the highest average N-nitrosamine concentration were confirmed in the gastric juice of patients after gastroenterostomy and after gastric resection with the Billroth II method, and the lowest values--in patients after highly selective vagotomy.

The clinical usefulness of the determinations of the zinc serum concentration at different stages of the breast cancer diagnostic process was evaluated in the present work. On the basis of the analysis of 182 women surgically treated because of this neoplasm, a statistically significant dependence was shown between the frequency of occurrence of hypozincemia and the progression of the cancer, its histological form, and the microscopic state of the axillary lymph nodes. The clinical usefulness was also shown by the determinations of the zincemia in the post-operative monitoring of patients with breast cancer. The critical value was also determined for the microelement concentration below which a statistically significantly high risk of occurrence of distant metastases appears.

In the last ten years advances in analytical methods have enabled the determination of xenobiotics in alternative material such as sweat, saliva, and hair. The aim of this study was to develop an analytical method and measure the concentration of the main opiates in serum saliva and hair of subjects from a detoxification and methadone treatment programme. The analytical strategy in the presented study, based on enzymoimmunoassay screening of opiates in urine and GC/MS confirmation, meets the needs of forensic and clinical toxicology. Blood and saliva samples from thirty seven patients and hair from twenty three with a history of intravenous opiate use were collected for analysis. The ranges of morphine in serum and saliva were 0-2081 and 0-208 ng/ml respectively; corresponding concentrations of codeine were 0-580 and 0-428 ng/ml respectively. The concentration of morphine, codeine and 6-MAM in hair of addicts ranged respectively from 0-32.4, 0-12.5 and 0-2.8 ng/mg. From the clinical toxicology point of view, hair analysis is supplementary to urine, serum or saliva determination, but in drug testing at the workplace it can play a crucial role.

Although it is known that drug addicts are a high-risk group for disruption of many homeostatic processes, little is know about changes in serum trace elements concentrations after taking the psychoactive substances. The aim of the study was to check the influence of the taking homemade heroin on serum level of copper. Blood samples were taken from 30 opiate addicts, and copper concentrations were measured by the means of atomic absorption spectrophotometry. The result of the study show that in the examined group, copper serum concentrations (1.35 mg/L) upon admission to the clinic were higher than in the control group (1.11 mg/L) but decreased during hospitalization (1.18 mg/L). There was no correlation between duration of stay at the hospital and changes in serum copper concentration.

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%.

The chemical-toxicological Laboratory of the Department of Clinical Toxicology carry on the analyses of xenobiotics in biological fluid collected from poisoned patient leaving in Krakow and south-eastern Poland. The evaluation of frequency of performed analyses in the years 1990-1999 shown that among psychoactive substances, ethanol is the most common reason of acute poisoning, followed by psychotropic drugs and drugs of abuse. The level of ethyl alcohol above 2 g/L was observed in more than 40% of patients. In evaluated period the number of barbiturates analyses dropped, benzodiazepines stayed on the same level. During this time evident increase of illicit drugs (amphetamines, opiates and THC) analyses was observed.

The aim of this study was to determine the concentration of zinc, copper and magnesium in the blood serum of drug addicts in order to ascertain whether drug abuse has an effect on the concentration of these metals. The study was carried out on a group of 33 addicts undergoing treatment at the Department of Clinical Toxicology, Collegium Medicum, Jagiellonian University in Kraków. The control group consisted of 22 young, healthy, drug free, male volunteers. Analyses were performed using flame atomic absorption spectrometry. The results demonstrate that zinc serum concentrations in the examined group of addicts before therapy (mean 0.82 mg/l) were reduced in relation to the control group (mean 1.12 mg/l), and was slightly enhanced after the detoxification process (mean 0.86 mg/l). The opposite effect was observed in the case copper serum concentration. The copper level in the group of addicts on admission to hospital (mean 1.35 mg/l) increased in relation to the control group (mean 1.11 mg/l) and was lower during hospitalisation (mean 1.18 mg/l). The concentration of magnesium in the serum of drug addicts did not change during therapy and was in the same range as in the control group (mean concentrations were 20.3 mg/l, 20.2 mg/l and 20.6 mg/l respectively).

The circadian changes in absorption, tissue distribution and elimination of amitriptyline after single intravenous (i.v.) and intragastric (i.g.) administration, as well as the differences in pharmacokinetic profile after multiple i.g. administration (at 10:00 and 22:00 h) during a 12 h dosing interval, were investigated. The circadian changes of pharmacokinetic parameters of amitriptyline such as AUC (serum and tissues), clearance (i.v. and i.g.), volume of distribution, biological half-life and bioavailability were estimated. Acrophases for clearance appeared between 19:00 and 21:00 h; the bioavailability was highest during the dark phase at around 04:00 h. Higher values of AUC in serum were observed at the beginning of the light phase. A circadian rhythm of tissue distribution (AUC, K(D)) of amitriptyline with acrophase in the dark phase was observed for brain (12 h period), lung and liver (24 h), but not for heart or kidney. After single (i.v. and i.g.) amitriptyline administration, concentrations of its major metabolite, nortriptyline, were negligible; however, after ten doses, nortriptyline serum and tissue levels were similar to the concentrations of the parent drug with higher values during the day (light phase).

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.

Tacrolimus is an immunosuppressive agent used for organ transplantation. Studies were performed to examine the influence of different perfusate hematocrits and albumin concentrations on hepatic extraction of tacrolimus. In vitro binding, efflux and influx between red blood cells (RBCs) and buffer or plasma, and rabbit liver perfusion with use of human erythrocytes were studied. In the range of hematocrits from 0.05 to 0.4, plasma concentrations of tacrolimus were not affected by increased albumin content. Increased hematocrit caused decreases in whole blood:plasma (buffer) concentration ratios. The binding capacity of drug with RBCs was independent of hematocrit, with a value of 440 ng/ml of RBCs; the binding affinity was 0.876 ng/ml using plasma or buffer. Diffusion of tacrolimus from RBCs to buffer was rapid with a clearance of 0.940 ml/min, and equilibration was achieved within 2 min. Diffusion in the opposite direction (buffer-RBCs) was slower with a clearance of 0.576 ml/min. In such diffusion studies, plasma produced a greater difference between efflux (1.70 ml/min) and influx (0.276 ml/min) clearances. During liver perfusion, the major factor regulating elimination of tacrolimus was hematocrit. Both well-stirred and parallel-tube models reflected a low extraction ratio drug with values of 0.15 and 0.17 for the 0.05 and 0.2 hematocrits. Intrinsic clearances were 8.43 and 17.44 ml/min for the well-stirred and parallel-tube models. Albumin had a negligible influence on liver extraction of drug. A model-building process of characterizing nonlinear RBC binding, RBC diffusion rates, and liver perfusion parameters allows the complexities of tacrolimus hepatic clearance to be dissected and shows that strong RBC binding can be artificially perceived as causing a high clearance of the drug.

The symptoms and clinical course of repeated poisonings with isopropyl alcohol in ethanol addicted 43-years old man is presented in the study. The blood and urine concentrations of isopropanol and acetone and also the blood ethanol concentration are given. The biological half-life of isopropanol calculated for the first 12 hours from admission to the Clinic was 6.9 hours. The biological half-life of acetone in the first 6 hours of hospitalisation was 5 hours, and then a considerable slowing down up to 29 hours was noted. The clinical symptoms, similar to ethanol poisoning, including strongly manifested catatonia and ketonuria without metabolic acidosis indicate the isopropanol intoxication. Hypokalemia should to be taken into consideration in treatment of isopropanol poisoning. An intravenous bicarbonates should be administered carefully e.g. when rhabdomyolysis occur.

Objective: To characterize the pharmacokinetics of the immunosuppressive agent tacrolimus (FK 506) in liver transplant patients., Methods: Patients (n = 16) were assessed during and after 1- to 3-day intravenous infusions followed by a 2-week course of oral dose therapy. Plasma and whole blood data were fitted simultaneously with equations accounting for nonlinear drug binding by red blood cells to generate clearance (CL) and volume of distribution (V)., Results: The maximum blood/plasma ratio of tacrolimus was 55.5 +/- 26.8 (SD) and half-life averaged 12.1 +/- 4.7 hours. The CL and V were relatively high based on plasma concentrations (CL, 1.7 L/hr/kg; V, 30 L/kg) and low based on whole blood (CL, 54 ml/hr/kg; V, 0.9 L/kg), with moderate variability (coefficient of variation, 34% to 49%) among the patients. Correlations of plasma CL and V with maximum blood/plasma ratios (ranging from 13 to 114) were strong (r = 0.65 and r = 0.73). Blood binding affects the disposition of tacrolimus, and plasma concentrations are indirectly and inversely related to red cell binding. The oral dose data for tacrolimus yielded a brief absorption lag time (tlag, 0.39 hour), a variable first-order absorption rate constant (ka, 4.5 +/- 3.0 hr-1), and consistent bioavailability (F, 25% +/- 10%). The area under the concentration-time curve versus 12-hour minimum concentration relationships for both whole blood and plasma were nearly linear, confirming the utility of trough values for monitoring drug exposure., Conclusion: This study provides pharmacokinetic guidelines for the use of tacrolimus in patients undergoing hepatic transplantation. Nonlinear blood binding is a major source of interpatient variation in the disposition of tacrolimus.

A whole blood lymphocyte proliferation assay was compared to a standard method requiring the isolation of lymphocytes from blood. Both methods were used to measure inhibition of proliferative responses of phytohaemagglutinin (PHA1)-stimulated human peripheral blood lymphocytes by tacrolimus (FK 506(1)), cyclosporine A (CsA1), rapamycin (RA1), dexamethasone (DEX1), prednisolone (PR1), and methylprednisolone (MP1). Three of the drugs studied (FK 506, CsA, and DEX) yielded similar IC50 values with both methods. The whole blood proliferation assay produced modestly lower IC50 values for RA, PR and MP. The whole blood lymphocyte proliferation method is simple and can be used when only limited volumes of blood can be obtained or isolation of cells gives unsatisfactory yields.

The influence of cimetidine on the activity of microsomal enzymes in vivo using the simple one-sample antipyrine test was investigated. The calculated antipyrine clearance unequivocally indicates the dose-dependent effect of cimetidine on the microsomal biotransformation of antipyrine. The IC50 of cimetidine inhibitory effect was 39.9 mg/kg. The duration of the effect was approximately 12 h and the lowest antipyrine clearance was observed 0.5 h following cimetidine administration. The in vivo results were confirmed by an in vitro study. Km for global metabolic processes of antipyrine in vitro was 1.3 mM. Vmax 9.1 nM/mg/min for control was decreased to 3.1 nM/mg/min after addition of cimetidine (4 mM). The inhibition constant of cimetidine determined by the method of Dixon, was 2.8 mM. Inhibition of antipyrine metabolism by cimetidine was noncompetitive.

Tacrolimus is a macrolide immunosuppressive drug undergoing clinical trials for organ transplantation. Whole animal studies were undertaken to assess the rabbit as an animal model for tacrolimus pharmacokinetics. The disposition of tacrolimus in rabbits following 0.5 mg/kg iv and 2.0 mg/kg po doses is similar to man. The apparent plasma clearance 1.67 liters/hr/kg is more than 5-fold higher than blood clearance 0.31 liters/hr/kg. The steady-state volume of distribution is 30.7 liters/kg for plasma and 6.3 liters/kg for whole blood. The bioavailability after oral administration calculated from plasma and whole blood is low with a mean value of 9.7%. The in vitro studies and fitting using a nonlinear red blood cell (RBC)-plasma binding/diffusion model showed slow diffusion of drug from RBC to plasma (t1/2 = 7 min, CLD = 0.085 ml/min). In perfused liver studies, the extraction ratio of tacrolimus from blood with hematocrit of 0.1 is low (0.20). However, extraction of drug from plasma is moderate (0.42), and plasma concentrations are elevated by an average of 28% because of redistribution of tacrolimus from RBC. This creates a lower apparent plasma clearance (DO/AUC) for equilibrated (30 min at 37 degrees C) samples (15.4 ml/min) compared with samples centrifuged within 5 min (22.1 ml/min). RBC efflux was accounted for using a comprehensive perfusion/diffusion model. The intrinsic metabolic clearance averaged 29.2 ml/min. Simulations showed that the apparent plasma clearance of tacrolimus is closely correlated with RBC binding capacity (whole blood:plasma ratio). Higher ratios caused greater apparent plasma clearance (lower concentration of tacrolimus in reservoir plasma) because strong binding of drug by erythrocytes prevents tacrolimus from diffusion into plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

An ultracentrifugation method was used for the determination of the tacrolimus (FK 506) free fraction in plasma. Samples of 400 microL were centrifuged for 6 h at 160,000 x g, and concentrations of [3H]tacrolimus were measured in the original plasma and in the second layer of the supernatant. The binding of tacrolimus in normal plasma averaged 73% and was independent of the drug concentration. Albumin (3.5%) binding averaged 44.4-57.0%, and alpha 1-acid glycoprotein (100 mg/L) binding averaged 39%. Hepatic transplant patients exhibited 72.0% +/- 3.6% binding of tacrolimus. Plasma protein binding is probably not an important factor in the disposition of tacrolimus.

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.

Cytochrome P-450 in liver microsomes plays a central role as a drug metabolizing enzyme. The sex-dependent differences in the properties of cytochrome P-450 have been extensively studied using liver microsomes, and marked differences have been found in microsomal metabolism of xenobiotic. Effect of pretreatment with phenobarbital, chrysene, lindane and polychlorinated biphenyls (Aroclor 1254) on the theophylline elimination in male and female rats was studied. Levels of theophylline were measured spectrophotometrically.

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.

In the present study we have examined the effect of treatment with benz(a)-anthracene (BaA), pyrene (P) and fluoranthene (Fl) on the total liver microsomal content of cytochrome P-450 and elimination of these PAH from blood in rats. The experiment was carried out on adult male rats Wistar breed. Oil solution of inducers: benz(a)anthracene, pyrene and fluoranthene in dose 20 mg/kg were administered individually one or threefold by gavage. 24 h after a single dose of PAH cytochrome P-450 content in rat liver determined by the method of Omura and Sato was the same as in control group. When PAH were administered p.o. for three consecutive days in the fourth day of experiment cytochrome P-450 content was increased from about 0.68 nM/mg protein to about 1.2 nM/mg. Since the increase of cytochrome P-450 may influence on elimination of xenobiotics we have determined affect PAH on their blood level after i.v. administration. One hour after BaA administration and two hours after Fl and P blood samples were collected. Concentration of PAH in blood was determined by gas-liquid chromatography. Pretreatment of rats with BaA decreased elimination of Fl, P, BaA from blood in comparison to the control rats. It indicated on the self-inducing effect of BaA on its own metabolism and inducing effect of metabolism other PAH. Pretreatment of rats with pyrene decreased elimination of BaA. It seemed that pyrene inhibited the oxidation of BaA in rat liver microsomes.

Pharmacokinetic studies indicate the diurnal rhythmicity of metabolism of many drugs. Partially it is a result of circadian variations of mixed function oxidase system, which metabolizes some drugs. The aim of the experiment was to evaluate the elimination rate phenacetin and antipyrine in different periods of day under standard light/dark (L/D) conditions (08.00-20.00/20.00-08.00). Studies were carried out on rats intragastrically treated with phenacetin in a dose of 0.42 mmol per kilogram of body weight or antipyrine in a dose of 0.17 mmol/kg at 14.00, 20.00, 02.00, 08.00 and 14.00 o'clock. The rate constants (k) were calculated on the basis of concentration of both substances in blood 2 and 3 hours after administration. Excretion of p-aminophenol in urine was determined in mentioned hours after administration of phenacetin in a dose of 0.28 mmol/kg per os. Differences of rates of elimination of both drugs were found. The maximum occurred at 10.00, and minimum at 22.00 o'clock, which indicate circadian periodicity of metabolism.

The pharmacokinetics of antipyrine in a dose of 20 mg/kg i.v. and cytochrome P-450 level in liver, were studied in control and pretreated rats with 1, 5, 25 ppm polychlorinated biphenyls in food for up to 120 days. The objective of this work was to quantitate the effects of low environmental levels of the contaminant and enzyme inducer (PCB) on the pharmacokinetics of antipyrine, a drug whose primary elimination route is liver metabolism. After 30 days of pretreatment only the 25 ppm treated rats showed any significant acceleration of antipyrine elimination. At the 60 and 120 days samplings, both the 5 and 25 ppm pretreatments show significant acceleration of antipyrine elimination. The changes in cytochrome P-450 lever were similar and no significant effects on body weight and volume of distribution was observed.

The investigations of the effect of some compounds belonging to the group of polycyclic aromatic hydrocarbons (PAH), e. g. benzo[a]pyrene, chrysene, fluorene and pyrene, on the elimination of theophylline injected i. v. into rats have shown that benzo[a]pyrene and chrysene accelerate the elimination of this drug (elimination rate constant in control group: 0.2504 h-1; after benzo[a]pyrene: 0.3626 h-1; after chrysene: 0.3582 h-1). The increase of theophylline elimination rate constant by chrysene depends on its dose, and this relationship is of sigmoid type in the dose range of 1-20 mg X kg-1. Besides, dependence of theophylline elimination rate constant on the time of chrysene dosing was also shown. After oral administration of theophylline the decrease of its amount reaching the circulation by 11% was also observed, which was caused by the influence of chrysene on the first-pass effect, beside its influence on the elimination rate.

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.