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Objective: The aim of the study was to evaluate the metabolic disturbances in ethanol dependent patients acutely poisoned with ethanol. This paper presents time profiles of ethanol, methanol, acetaldehyde, acetone, isopropanol and n-propanol and quantitative relationship between their concentrations and elimination rates. Methods: 171 patients acutely poisoned with ethanol (22 women, 149 men), aged 16-75 years (mean 41 [+ or -] 11.6), with a history of alcohol use ranging from one year to more then ten years, participated in the study. The clinical diagnosis was done based on a patient interview, and physical, psychological and psychiatric examination. The liver state was examined based on biochemical tests. Blood samples for toxicological study were taken just after admission to the Department of Clinical Toxicology and after 6, 18 and 24 hours. Concentration of ethanol and other compounds in a series samples were measured using headspace gas chromatography. Chromatograms were recorded and calculations were done using the Turbochrom computer programme. Results: In all patients the addiction was confirmed. The biochemical markers of liver impairment were changed-ALT activity was raised in 62.1% of patients, ALT in 53.1%, in 40.3% of patients bilirubin concentration was elevated, GGT activity was normal only in 36.8% of the studied group, albumin concentration was decreased in 32.1% of patients. At the time of admission average ethanol concentration in blood was 3.06 [+ or -] 1.15 g/L and ranged from 0.76 to 6.6 g/L. Except for a few cases other volatile compounds were found in the blood of these patients. The elimination rate constant (zero order) of ethanol ranged from 0.09 to 0.54 g/h/kg (mean 0.262 [+ or -] 0.077, n = 122). For patients with a higher ethanol concentration at the beginning, faster ethanol elimination was observed. Average methanol concentration at admission was 28.6 [+ or -] 38.7 mg/L, ranged from 0.4 to 324.4 mg/L. The concentration of methanol decreased very slowly when ethanol concentration was high. After 6 hours, while the mean ethanol concentration was around 1.5 g/L, the rate of methanol elimination increased. The calculated elimination rate between 6 and 18 hour was around 0.2 [h.sup.-1]. The [T.sub.1/2] of methanol was 3.36 [+ or -] 1.94 h (n = 79) and was independent of ethanol concentration at 6 hour. The mean concentration for other studied compounds was: acetaldehyde 5.56 [+ or -] 3.68 mg/L, acetone 10.74 [+ or -] 25.5 mg/L, isopropanol 4.56 [+ or -] 8.9 mg/L and n-propanol 1.09 [+ or -] 1.3 mg/L. The elimination rate constants for these compounds ranged from 0.137 [h.sup.-1] for n-propanol (n = 70), 0.144 [h.sup.-1] for isopropanol (n = 57) to 0.246 [h.sup.-1] for acetaldehyde (n = 73). During the whole study period (24 hours), the acetone concentration was elevated and stayed at the same level-around 10 mg/L. Conclusion: The presence of other alcohols and volatile compounds in the blood of ethanol addicted patients is common. There is not significant correlation between the ethanol concentration and other determined compounds. The elimination of methanol in addicted patients can start when the concentration of ethanol is still high., Zuba D, Piekoszewski W, Pach J, Groszek B, Parczewski A. Department of Clinical Toxicology College of Medicine Jagiellonian University, Department of Analytical Chemistry Jagiellonian University, Institute of Forensic Research, Krakow, [...]

Objective: Before considering problems in the field of toxicokinetics we must first define what we mean by this concept. In the context of research into new drugs, toxicokinetics should be understood as kinetic studies aimed at assessing risk from drugs through toxicological trials on animals (pre-clinical trials). Some researchers, who wish to avoid using the term pharmacokinetics when referring to absorption and disposition studies concerning xenobiotics which are not medicines, use the term toxicokinetics. Clinical toxicologists in turn use this term to refer to studies of the kinetics of medicines/xenobiotics in acute poisoning cases. If we accept this definition we should ponder where the data for toxicological elaborating/modeling come from. Only in a few cases can the data originate from planned clinical studies involving volunteers; furthermore only relatively non-toxic compounds and relatively small doses can be applied. Most papers on kinetics are based on xenobiotics determinations in physiological fluids carried out for diagnostic purposes, sometimes `enriched' in terms of numbers of determinations (having in mind future scientific papers). The aim of this presentation is an attempt to answer the question: `Can results of routine diagnostic studies be applied to kinetic studies/ toxicokinetic modeling, and not just to the calculation of basic pharmacokinetic parameters?' A fundamental problem encountered when applying such results in toxicokinetic modeling is uncertainty as the future dose and the time of its taking. Attempts to solve this problem are presented in this paper: the application of pharmacokinetic models, population pharmacokinetic and neuronal networks. Material and methods: The pharmacokinetics of carbamazepine were studied using data from routine toxicological analysis of 57 poisoned patients and of 20 patients who were administered carbamazepine in therapeutic doses (3 x 200 mg) for the first time in their life, so carbamazepine monitoring was done for toxicological diagnosis or for drug therapy monitoring. Patients were given carbamazepine at 6 a.m., 12 p.m., and 6 p.m. The blood samples were collected at 3 and 6 p.m. just before administration a new dose of the drug. Basic information on amount and time of ingestion in acutely poisoned patients were known from interview and laboratory determinations. The basic pharmacokinetic parameters of carbamazepine in patients treated with carbamazepine were calculated using the one-compartment model. The data from poisoned patients were analyzed using the non-linear mixed effects model (NONMEM) program designed for population pharmacokinetic parameters. Also the neuronal network was applied for pharmacokinetic calculation in poisoned patients. Results: The pharmacokinetic parameters of carbamazepine in patients treated with this drug were: [t.sub.1/2] = 27.7 [+ or -] 8.7 h; Cl = 0.0681 [+ or -] 0.0281 L/h/kg, [V.sub.d] = 4.0 [+ or -] 1.8 L/kg and for carbamazepine poisoned patients respectively: [t.sub.1/2] = 39.3 [+ or -] 17.2 h; Cl = 0.08 [+ or -] 0.0171 L/h/kg, [V.sub.d] = 2.9 [+ or -] 0.5 L/kg. Conclusion: The simple compartment models can be used for pharmacokinetic calculation after administration of drug in therapeutic doses however the population pharmacokinetics and neuronal network are well fitted in toxic concentrations. Piekoszewski W(1) (1) Department of Clinical Toxicology Collegium Medicum Jagiellonian University and The Institute of Forensic Research and Laboratory of Clinical Toxicology and Pharmacokinetics, Rydygiers Hospital Krakow, Poland

Tacrolimus (FK 506) is used for treatment of various organ transplantations in combination with corticosteroids. Rabbits are a good animal model for pharmacokinetic studies of these drugs. The i.v. administration of methylprednisolone (MP; 1.25 mg/kg) (sodium succinate) at 0.5 hr after tacrolimus (0.15 mg/kg) did not influence the disposition of these drugs in rabbits. Clearances of MP were 0.45 liters/hr/kg after given alone and 0.48 liter/hr/kg after tracrolimus. The plasma and whole blood clearances of tacrolimus were 2.18 and 0.21 and 2.35 and 0.19 liters/hr/kg after separate and joint administration with the steroid. The concentrations of corticosterone were variable in all groups and was not useful as a pharmacodynamic parameter. Whole blood histamine concentrations as a marker for basophils did not change after drug administration, but increased over several weeks of experiments. Helper-T cells in rabbits as in humans show a circadian rhythm with an acrophase at 1:00 A.M. MP and tacrolimus decreased the number of circulating helper-T cells with IC50 values of 23 ng/ml for MP and 6.7 ng/ml for tacrolimus. After coadministration of these drugs, an interaction occurs, but the nature (additive or antagonistic) of this interaction was not clear. The IC50 of tacrolimus for in vitro inhibition of lymphocyte proliferation was 0.39 ng/ml (0.47 nM) and 1.02 ng/ml (2.73 nM) for MP. The maximum percentage of inhibition was 94.6% for tacrolimus and 64.9% for MP. The interaction between low concentrations of tacrolimus (0.1-0.3 ng/ml) and MP was additive, but mild antagonism was observed at higher concentration of tacrolimus (1 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)