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Biomedical subjects

L Vereczkey

Publications and source records attributed to L Vereczkey.

At least 37 records · Page 2Linked to original sources
PubMed1994

The effect of phenobarbital and dexamethasone coadministration on the activity of rat liver P450 system.

Phenobarbital, the potent inducer of CYP2B and CYP3A, and dexamethasone, that induces CYP3A, are not able to elevate p-nitrophenol hydroxylase activity of CYP2E1. However, rats treated with phenobarbital and dexamethasone in combination showed threefold increase in p-nitrophenol hydroxylation and the activity correlates with an elevated amount of a 53.000 dalton protein. Biosynthesis of mRNA and P450 protein is required for the induction. 3-amino-1,2,4-triazole and anti CYP2E1 IgG inhibition studies show that CYP2E1 is not responsible for enhanced p-nitrophenol hydroxylation, but the residual activity indicates the participation of other isozyme(s). As a result of double induction, changes in the amount of CYP2E1 of microsomes were not detected by Western blot analysis compared to untreated rat liver microsomes.

Aminopyrine N-Demethylase↗
PubMed1994

Pharmacokinetic study on a new antiischaemic agent (BRLP-42).

In the present study the pharmacokinetics of BRLP-42--a new antiischaemic agent--was investigated in dogs and rats. Plasma concentrations were measured by HPLC. After intravenous application the curves can be characterized by a two-compartment open pharmacokinetic model. The central volume of distribution (Vcentr.) is large (1.07 +/- 0.14 l/kg in dogs and 2.74 l/kg in rats), the first elimination half-life (t1/2 alpha) is 5.47 +/- 1.67 min in dogs and 13.7 min in rats. These facts indicate rapid and large tissue distribution. The excretion and/or metabolic elimination of BRLP-42 resulted in short second elimination half-life (t1/2 beta = 41.45 +/- 2.34 min in dogs and 43.8 min in rats). After oral application high individual variability can be seen. This fact may be due to the different rate and/or extent of absorption process. The plasma level curves can be characterized by a one-compartment open pharmacokinetic model. The absorption seems to conceal the distribution phase of the kinetic curve. The absorption half-life was short (t1/2a = 17.36 +/- 5.90 min in dogs and 2.7 min in rats). The bioavailability was 40 +/- 8% in dogs and 28% in rats. The elimination half-life (t1/2e = 28.77 +/- 0.88 min in dogs and 30.1 min in rats) is connected dominantly with metabolic elimination and/or excretion of BRLP-42. In the cases of intravenous as well as oral administrations the plasma concentrations decreased under the limit of quantitation by 4-6 hours in dogs and 4 hours in rats after treatments.

Administration, Oral↗
PubMed1993

Combined action of phenobarbital and dexamethasone on the activity of rat liver P450 system.

Phenobarbital and dexamethasone are potent inducers of the same cytochrome P450 form, CYP3A1, but the mechanism of action is not quite clear. If the mechanism of induction by phenobarbital and dexamethasone is different, additive effect may be observed in the specific activities of CYP3A1: ethylmorphine or aminopyrine N-demethylation of liver microsomes from rats treated with phenobarbital and dexamethasone in combination. The results of recent work could not display differences in CYP3A1 activities between the groups of animals single-administered and coadministered with phenobarbital and dexamethasone. However, p-nitrophenol hydroxylation surprisingly increased threefold as a result of double induction. 3-amino-1,2,4-triazole inhibition study shows that CYP2E1 is responsible for 60% of enhanced p-nitrophenol hydroxylase activity, but the residual 40% indicates the participation of other isoenzyme(s).

Animals↗
PubMed1993

[Pharmacokinetic studies of 14C-labeled epervudine in rats].

The characteristics of absorption, distribution and elimination of 14C-labelled epervudine were studied in rats treated with 10 mg/kg doses orally and intravenously. The blood level curves were analyzed by appropriate pharmacokinetic models. The results of oral treatment showed a rapid absorption of the radioactivity from the gastrointestinal tracts of the animals (tmax (0.75 h). The elimination rate of radioactivity from blood was fast (t1/2 el = 5.53 h). Blood level curves were characterized by a rapid initial distribution phase after intravenous treatment (t1/2 alpha = 0.17 h). Subsequently, the rate of elimination became slower and the concentration of radioactivity remained at a low level between 2 and 24 hours after the treatment. Studies of distribution did not reveal any specific tissue accumulation. As shown by excretion studies, the elimination of the radioactivity was fast following both the oral and intravenous administration. Within 24 hours ca. 50% excreted with urine and ca. 20% with feces. The ratio areas under blood level curves demonstrated an absorption of 70% (AUCpo: AUCiv x 100).

Administration, Oral↗
PubMed1993

[Pharmacokinetic studies of epervudine in rats using HPLC].

Pharmacokinetic properties of active substance of Hevizos ointment (Epervudine) were studied in rats after intravenous, oral and dermal applications. The animals received 10 mg/kg of Epervudine intravenously and orally. For checking of dermal absorption 220 mg of ointment (containing 0.8% of Epervudine) was applied. An HPLC method was developed for determination of Epervudine concentrations in serum. The method meets the requirements of precision and accuracy of the kinetic measurements (i.e. CV% is less than 20%) within the concentration range of 50-10,000 ng/ml. The mean serum concentration-time curve after i.v. administration can be characterized by a two-compartment open pharmacokinetic model. The first and second elimination half-lives (t1/2 alpha and t1/2 beta) are 0.14 and 0.31 hours, respectively. These values indicate fast distribution and elimination of compound studied. In the case of oral administration the absorption process conceals the fast distribution, so the mean serum concentration-time curve can be characterized by a one-compartment open pharmacokinetic model. The absorption of Epervudine starts practically prompt. The absorption half-life (t1/2a) is 0.11 hours. Highest serum concentrations were measured from 20 to 90 minutes after treatment. The elimination half-life (t1/2e) is 1.53 hours. The ratio of areas under serum level curves following oral and intravenous administration proves a good bioavailability (90%) of Epervudine. After dermal application Epervudine does not absorb.

Administration, Oral↗
PubMed1993

Chromogen-substrate assay--as a tool for monitoring a new thrombin inhibitor.

The N-methyl-D-phenylalanyl-L-prolyl-arginine-aldehyde sulfate tripeptide-aldehyde (GYKI-14766) is an anticoagulant with specific thrombin inhibitor action. The molecule proved to be effective in rabbits, rats and dogs upon i.v. administration. Chromogen-substrate assay was developed for monitoring of biologically active tripeptide-inhibitor GYKI-14766 in plasma. The assay based on the inhibition of the active center of the thrombin enzyme, so it is suitable also for the assay of all those active metabolites which inhibit thrombin by a mechanism similar to the active parent compound. The chromogen substrate assay was performed in a range of 0.625-10 micrograms/ml GYKI-14766 in dog plasma. The assay was employed in pharmacokinetic study in dogs after i.v. administration. The data obtained in the chromogen-substrate assay were analyzed according to a one-compartment model. The major parameters of the plasma level studies were: D/V = 8.6 microEqv/ml t1/2 = 30.8 min AUC = 380 min microEqv/ml.

Amino Acid Sequence↗
PubMed1992

Pharmacokinetic and metabolism studies on girisopam by chromatographic and spectrometric methods in humans.

Girisopam possesses selective anxiolytic action without muscle relaxant and anticonvulsive activity. After a 100-mg oral dose of 14C-labelled girisopam to seven male subjects, the mean recovery of 14C radioactivity was 51% in urine and 33% in faeces. A high-performance liquid chromatographic method has been developed for studying girisopam in single-dose pharmacokinetic studies. The serum extract was chromatographed on a normal-phase column using a mobile phase of hexane-ethanol-diethyl ether (66:9:25, v/v) and ultraviolet detection at 235 nm. The recovery was 60% and the detection limit was 3 ng/ml, using 1 ml of serum. After a 20-min delay, girisopam is rapidly absorbed. After reaching a mean serum level of 178 ng/ml at a mean time of 2.0 h, the serum concentration of girisopam decreased with a mean elimination half-time of 22.2 h. The metabolites were separated by high-performance liquid chromatography, radio thin-layer chromatography and gas chromatography. Their structures were determined by liquid chromatography-mass spectrometry, mass spectrometry and gas chromatography-mass spectrometry. Their chemical structures were confirmed by comparison with synthesized reference compounds. The major urinary metabolites were 7-demethylgirisopam (I), 4'-hydroxygirisopam (II) and 4-hydroxymethyl-4-demethylgirisopam (III), which were in conjugated form, and 4-carboxy-4-demethylgirisopam (V), a compound with an open-chain structure (VII) and traces of 4-demethyl-4-oxogirisopam (VIII) and 4-hydroxymethyl-4-demethylgirisopam (III), which were in non-conjugated form. The metabolic profile in the serum consisted predominantly of the glucuronides of I, II and III. The non-conjugated metabolites were the metabolite with the open-chain structure (VII), III and V. Besides the parent compound, the faeces sample contained conjugates of I and II.

Adult↗
PubMed1992

[Pharmacokinetics and metabolism of pipecuronium bromide (Arduan)].

The pharmacokinetics of pipecuronium bromide (Arduan) studied in animals (rat, dog, cat) and in humans can be described by a two-compartment open model. The elimination half-life in animals was found to be around 40 min, in humans between 44-137 min. The main route of elimination is the excretion of the unchanged molecule in urine. In kidney patients the elimination becomes longer. The metabolism in the elimination is less important, in rats 3-hydroxy-, 17-hydroxy and 3,17-dihydroxy metabolites have been identified.

Androstane-3,17-diol↗
PubMed1992

[Cytochrome P-450: structure, function, induction and practical significance].

The liver contains a series of microsomal hemoproteins, called cytochromes P-450 which are mixed-function oxygenases involved in the metabolic oxygenation of diverse xenobiotic chemicals (drugs, pesticides, etc.). This enzyme system converts lipophilic foreign compounds into more water soluble products, thereby facilitating their elimination from the body. In general, cytochrome P-450-catalyzed oxidation results in detoxification, however the cytochromes P-450 can also convert certain xenobiotics to more toxic or carcinogenic products. Many of the individual isoenzyme forms of cytochrome P-450 are inducible by a wide variety of chemicals. After induction the concentration of total cytochrome P-450 in liver microsomes and the activity of different cytochrome P-450 forms increase. Elevated levels of cytochrome P-450 are the result of multiple mechanisms. Increased transcription of P-450 genes is a major mechanism of cytochrome P-450 induction. Higher levels of specific mRNAs are detectable soon after treatment with either "phenobarbital-like" or polycyclic aromatic compounds. Although increased transcription plays some role in the induction of cytochromes P-450 by other inducers like pregnenolone-16 alpha-carbonitrile (PCN)/glucocorticoids and "ethanol-type" compounds, post-transcriptional events are also very important. Cytochrome P-450 induction can be achieved by message stabilization and enhanced transport of mRNA from the nucleus to the cytoplasm that also increase the specific mRNA levels at the site of protein synthesis. Elevated cytochrome P-450 levels may also result from protein stabilization. Stabilization of cytochrome P-450 protein and/or mRNA are the main processes of induction by PCN/glucocorticoids and ethanol-type inducers. Although these mechanisms exist, they do not seem to be important in the induction by "phenobarbital-like" and "3-methylcholanthrene-like" inducers. The fact that induction is produced by a large variety of xenobiotics and is mediated by multiple mechanisms suggests that cytochrome P-450 system can provide increased protection for organisms in potentially hostile chemical environment. Since cytochrome P-450 induction is a characteristic response to chemicals for various living organisms ranging from microorganisms to man, it seems to be an adaptive mechanism for organisms to increase the chance for survival.

Cytochrome P-450 Enzyme System↗
PubMed1991

High-performance liquid chromatographic method for the determination of RGH-5702 in plasma samples.

A quick and selective high-performance liquid chromatographic method has been developed for the determination of RGH-5702 in plasma samples. A simple one-step extraction is used followed by reversed-phase chromatography and UV detection. This method allowed the separation of the compound and internal standard within 7 minutes. Validation of the method was performed prior to the assay of samples and continued throughout the study. Acceptable accuracy and precision was achieved at all concentrations investigated. The quantitation limit was 20 ng/ml using 1 ml of plasma. The method has been applied to the analysis of plasma samples from toxicokinetic studies in dogs.

Animals↗
PubMed1989

Simple high-performance liquid chromatographic method for the determination of tolbutamide and its metabolites in human plasma and urine using photodiode-array detection.

A high-performance liquid chromatographic method has been developed for the determination of tolbutamide and its metabolites in human plasma and urine. The compounds examined were extracted with diethyl ether from the acidified biological fluid. Chlorpropamide was used as internal standard, and 235 nm was chosen as the wavelength for diode-array detection. A study of the relationship between the capacity factor and the mobile phase composition and pH showed that acetonitrile-2-propanol-0.1% orthophosphoric acid (17: 17: 66, v/v) was the best eluent on a C8 reversed-phase column. The method is precise, sensitive and suitable for pharmacological investigations.

Chromatography, High Pressure Liquid↗
PubMed1988

Mass spectrometric characterization of some human metabolites of flumecinol.

The mass spectrometric behaviour of six human metabolites formed by hydroxylation in various positions of the alpha-ethyl group or/and on the phenyl ring of 3-trifluoromethyl-alpha-ethyl-benzyhydrol (flumecinol) and seven related compounds has been studied. The electron impact mass (EI) spectra of these compounds show significant and characteristic effects of substituents, but many of them suffer from weakness or even from absence of the M+. peak owing to the very facile primary loss of the alpha-aliphatic chain, i.e. no direct information can be obtained about the size of the molecule and that of this chain. It is demonstrated for derivatives possessing a hydroxylated alpha-ethyl group that the difficulties in structural characterization due to the lack or weakness of M+. and [M + H]+ peaks in their EI and chemical ionization mass spectra, respectively, can be overcome by studying their silyated or boronated derivatives. Furthermore, silyation enables us to obtain a clear base for distinction of the primary and secondary alcohols of this type.

Benzhydryl Compounds↗
PubMed1987

Effect of age on the pharmacokinetics of vinpocetine (Cavinton) and apovincaminic acid.

The pharmacokinetics of vinpocetine and its main metabolite, apovincaminic acid (AVA), were studied in the aged. Vinpocetine was eliminated with a mean half-life of 2.12 +/- 0.51 h. Total plasma clearance (CL) and distribution coefficient (delta) of the parent drug were 2.2 +/- 0.9 l.kg-1.h-1 and 6.7 +/- 3.7 l.kg-1, respectively. The CL and delta of vinpocetine differed significantly from young subjects but the elimination half-life was not altered. Significant changes in the elimination half-life and plasma clearance of AVA were found, perhaps because of the physiological decrease in renal function.

Adult↗
PubMed1987

Gas-liquid chromatographic method for the determination of tolperisone in human plasma: pharmacokinetic and comparative bioavailability studies.

A new capillary GLC method for the determination of tolperisone in human plasma was developed. Pharmacokinetic and comparative bioavailability studies were carried out after i.v. administration and after oral administration of two different preparations of tolperisone. After i.v. administration of the drug the elimination half-life was found to be 1.55 +/- 0.7 h (mean +/- S.D.), the apparent volume of distribution to be 5.1 +/- 1.0 l/kg (mean +/- S.D.) and total body clearance to be 140.8 +/- 33.8 l/h (mean +/- S.D.). The oral bioavailability was found to be 22.3 +/- 6.3% for Mydeton tablets and 16.7 +/- 8.9% for Mydocalm tablets. There was no significant difference between the bioavailability of two oral tablets.

Journal Article↗
PubMed1987

Metabolism of flumecinol in humans.

1. The metabolism of 14C-flumecinol (3-trifluoromethyl-alpha-ethyl-benzhydrol) was studied in volunteers after a single oral dose of 100 mg (11.1 MBq; 300 microCi). Radioactivity excreted in urine was 78.8 +/- 6.0% of dose and in faeces was 12.0 +/- 5.3% dose in 120 h. 2. Unchanged flumecinol was not excreted in urine, but was present in faeces unconjugated (1.2% dose) and as conjugates of glucuronic and sulphuric acids (10.8% dose). 3. Enzymic hydrolysis showed that all urinary metabolites were conjugated with glucuronic and/or sulphuric acids (77.8% dose). Unconjugated urinary metabolites were not found. 4. The major route of flumecinol metabolism was hydroxylation of the alkyl side chain and/or the phenyl group followed by conjugation. 5. Both the CF3-group and the skeleton of the original compound remained intact during metabolism.

Adult↗