Effect of ribonuclease on pigeon liver ribosomal ribonucleic acids.
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Animals↗
Biomedical subjects
L Vereczkey
Publications and source records attributed to L Vereczkey.
RNase sensitivity of messenger and ribosomal RNA in pigeon liver polysomes.
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Amino Acids↗
The hippocampal electrical correlates of the homeostatic regulation of motivation.
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Animals↗
The pharmacokinetics and metabolism of N-desmethyl-N-formyl-leurosine (F-leurosine) in the rat.
Absorption, tissue distribution, excretion, protein binding, and the metabolism of 14C labelled F-leurosine were studied in the rat. A triphasic curve for the disappearance of the drug from blood was found. The bile was the major route of excretion: 80% of radioactivity was recovered in the bile during the first 28 h after i.v. administration. 54% of the F-leurosine binds, in the concentration range of 0.1 mumol/1-0.5 mmol/l to plasma proteins. The TLC and HPLC data suggested that the bile of rats administered [14C]-F-leurosine contained either none or only small amount of metabolic products, which were most probably due to chemical decomposition rather then metabolism. Rat liver homogenates did not metabolize [14C] F-leurosine to any detectable extent.
Animals↗
Pharmacokinetics of vinpocetine and apovincaminic acid in patients with impaired renal function.
Effects of renal insufficiency on the pharmacokinetics of vinpocetine and its main metabolite, apovincaminic acid (AVA) were investigated in the present study. The elimination rate constant, half-life, clearance, area under the curve and volume of distribution were measured and compared with reported values for subjects with normal renal function. Previous investigations have shown that the elimination half life of vinpocetine was 2.54 +/- 0.48 hours and half-life of AVA was 3.66 +/- 1.56 hours in healthy volunteers after i.v. administration of 10 mg vinpocetine.
Adult↗
Pharmacokinetics and metabolism of vincamine and related compounds.
The pharmacokinetics and metabolism of vincamine, vinpocetine, methylene-methoxy-apovincaminic acid ester and eburnamine have been reviewed. The main route of elimination for vincamine, vinpocetine and methylene-methoxy-apovincaminic acid ester is ester cleavage and conjugation in the case of eburnamine. Vincamine and its derivatives show significant differences in metabolic pathway and their elimination is rapid in the species studied. Emphasis has been placed on the analytical methods used for monitoring these drugs in biological systems.
Animals↗
Pharmacokinetics of vinpocetine and its main metabolite apovincaminic acid before and after the chronic oral administration of vinpocetine to humans.
The pharmacokinetics of vinpocetine (Cavinton) and of its main metabolite apovincaminic acid (AVA), has been studied in 5 healthy male volunteers after the administration of 3 x 5 and 3 x 10 daily doses of vinpocetine for seven days. The pharmacokinetic curves of both vinpocetine and AVA have been determined prior to the chronic administration and on the last day of the treatment, whereas between the 2nd and 6th days, concentration was measured once daily. On the basis of these pharmacokinetic studies it can be concluded that both vinpocetine and AVA show linear pharmacokinetics at the doses used and that there is no accumulation or autoinduction.
Adult↗
Study on the absorption of vinpocetine and apovincaminic acid.
The absorption of vinpocetine (Cavinton) and apovincaminic acid, compounds showing a marked difference in their physico-chemical properties, was studied in rats in in situ loop experiments by using radiolabelled compounds. In the case of apovincaminic acid, the investigations also involved the estimation of the portion of radioactivity excreted in urine and faeces after i.v. and p.o. administration of the compound. According to our results, it can be concluded that both vinpocetine and apovincaminic acid are absorbed from the gastrointestinal tract--apovincaminic acid mainly from the stomach, while vinpocetine is absorbed from the small intestine.
Administration, Oral↗
The effect of ipriflavone and its main metabolites on theophylline biotransformation.
The effect of ipriflavone and its major metabolites, 7-hydroxy-isoflavone and 7-(1-carboxy-ethoxy)-isoflavone on theophylline metabolism was examined in vitro in human liver microsomes. The compounds inhibited the N-demethylation to 1- or 3-methylxanthine, the major pathway of theophylline metabolism. The effect showed concentration dependence. The oxidation of theophylline to 1,3-dimethyluric acid was slightly affected by ipriflavone and its metabolites and the effect was non-specific. Results indicate that the reduction of theophylline clearance by concomitant ipriflavone administration observed by Takahashi et al. [Takahashi J., Kawakatsu K., Wakayama T., Sawaoka H. (1992): Elevation of serum theophylline levels by ipriflavone in a patient with chronic obstructive pulmonary disease. Eur. J. Clin. Pharmacol., 43, 207-208] is primarily due to an interaction of the inhibitory ipriflavone and/or its metabolites with cytochrome P450 enzyme(s) that mediate N-demethylation of theophylline.
Analgesics↗
Interaction of theophylline and ipriflavone at the cytochrome P450 level.
The effect of ipriflavone administered at a dose of 25 mg/kg and 100 mg/kg and coadministered with theophylline was investigated in selective assays of particular P450 isoenzyme activities. Significant changes could be detected in the activities of CYP2E1 and CYP3A in liver microsomes from male Wistar rats treated with ipriflavone. Induction of CYP2E1 was shown by aniline or p-nitro-phenol hydroxylation as a result of ipriflavone treatment. Aniline hydroxylation activity of CYP2E1 was induced by theophylline + ipriflavone (100 mg/kg) coadministration as well. It should be noted that theophylline does not cause alteration in CYP2E1 activity. On the other hand, ipriflavone inhibited ethylmorphine and aminopyrine N-demethylation activities catalysed by CYP3A. An additional effect in the inhibition of aminopyrine N-demethylation could be observed in microsomes from theophylline + ipriflavone treated groups. Our results suggest that the decrease in theophylline metabolism increasing level of serum theophylline of theophylline-treated patient during ipriflavone administration [Takahashi J. et al. (1992): Eur. J. Clin. Pharmacol., 43, 207-208] may be related to CYP3A inhibition by ipriflavone.
Alkylation↗
The in vitro biosynthesis and stability measurement with agyl-glycuronide isoformes of the main metabolite of ipriflavone.
The formation and stability of 1-beta-glucuronide conjugate of the main metabolite of ipriflavone [7-(1-carboxy-ethoxy)-isoflavone] (CI)--were studied by using liver microsomes, hepatocytes, and isolated perfused liver of untreated and 3-methylcholanthrene (MC) treated dog and rat, and human liver microsomes. MC treatment enhanced the rate of conjugation twice as much as that of the control in the microsomes of both dogs and rats. Conjugation of CI by microsomes results in two metabolites, both sensitive to pH and temperature. Other two glucuronide forms appeared in experiments with hepatocytes and perfused liver. Mass spectrometry supported. The conclusion, assumption that both metabolites produced by microsomes are glucuronide conjugate isoforms of CI, and that they could be distinguished according to the intensity of peaks on FAB-MIKE spectra. The beta-glucuronidase enzyme hydrolysed only the 1-beta-glucuronide isomer, the other, migrated form remained unchanged. D-saccharic-acid-1,4-lactone, a specific inhibitor of beta-glucuronidase enzyme, decreased the rate of enzymatic cleavage. Standard curves of CI were prepared by HPLC, and 1-beta-CI-glucuronide was quantified according to the amount of CI formed by hydrolysis. The stability of conjugates greatly depends on pH and temperature, and the rate of degradation and isomerization is sensitive to the value of both. Lowering the pH from 7.4 to 5.0 and the temperature from 37 degrees C to 18 degrees C increased the stability of glucuronides. Increasing the pH to 12.0 results in very rapid acyl migration and hydrolysis.
Animals↗
Effect of phenobarbital and spironolactone treatment on the oxidative metabolism of antipyrine by rat liver microsomes.
The effects of pretreating rats with the inducers, phenobarbital or spironolactone, on the formation rate of the three major oxidative metabolites of antipyrine in vitro by hepatic microsomal fractions have been investigated. Both inducers reduced the rate of 3-methylhydroxylation of antipyrine by approximately 50%. In contrast, N-demethylation and 4-hydroxylation were enhanced 1.7-fold and 3.4-fold, respectively, in case of phenobarbital induction and 1.4-fold and 2.6-fold, respectively, following spironolactone treatment. To elucidate the role of some cytochrome P450 isoenzymes in the production of the three major metabolites of antipyrine, the effects of form selective enzyme inhibitors on antipyrine oxidation were also studied. Troleandomycin did not alter 3-methylhydroxylation but reduced both N-demethylation and 4-hydroxylation of antipyrine in microsomes from induced rat liver. Cimetidine and chloramphenicol decreased the rate of formation of all three metabolites in microsomes from induced and uninduced animal livers as well. Chloramphenicol seemed to be the most potent inhibitor of in vitro antipyrine oxidation. Alpha-methyldopa significantly enhanced the rate of formation of 4-hydroxyantipyrine and slightly reduced the rate of N-demethylation and 3-methylhydroxylation. According to the data obtained with microsomes from uninduced rat livers, the formation of the three major metabolites of antipyrine is extensively mediated by CYP2C11/C6. In microsomes from induced animal liver, CYP2B and CYP3A may contribute to both N-demethylation and 4-hydroxylation of antipyrine.
Animals↗
In vitro-in vivo correlation of the pharmacokinetics of vinpocetine.
Vinpocetine is extensively metabolized in rats, dogs and humans, and the plasma clearance approximates the hepatic plasma flow in each of the species. In vitro degradation studies with hepatocytes have shown that the activity of human hepatocytes is about one order of magnitude higher than the activity of dog hepatocytes, and two orders of magnitude higher than that of rat hepatocytes. These differences can explain the differences in bioavailabilities of vinpocetine in the three species (52% in rats, 21.5+/-19.3% in dogs and 6.2+/-1.9% in humans). In dogs and humans, the compound seems to be metabolized exclusively in the liver whereas in rats extrahepatic metabolism seems also to be important. The in vivo clearance predicted from the activity of hepatocytes is in good agreement with the values measured in vivo in the case of humans and dogs. The estimated values for bioavailability showed good correlation with in vivo data in each species if the free drug ratio was assumed to equal 1.
Animals↗
[In vivo bioequivalence study of Sulpirid (GYKI-Alkaloida) and Dogmatil fort (Delagrange) 200 mg sulpiride tablets in healthy volunteers].
A single-dose, "crossover" bioequivalence study was conducted in healthy volunteers by comparing sulpiride serum levels after oral administration of the Test Product Sulpiride (200 mg) (GYKI-Alkaloida) in fasting subjects with those produced after oral administration of a marketed reference product (200 mg) (Delagrange Co., France). Statistical comparisons of Cmax, Tmax and AUC0-infinity have been performed utilizing ANOVA with subject, group, subject within group, period and product as sources of variance. No significant differences between the Test Drug and the Reference Drug considering the pharmacokinetic parameters Cmax, Tmax and AUC0-infinity were found. The 95% confidence intervals were as follows: AUC0-infinity: -20.46% and 31.19%, Cmax: -28.05% and 26.65% and Tmax: -43.53% and 20.67%. In the study for the analysis of Sulpiride a specific HPLC procedure with uv detection (lambda = 228 nm) and an internal standard were applied according to P. Nicolas et al. with modification. Sulpiride levels in serum reached a maximum at 4.4 hr +/- 1.5 (S.D.) following administration of Sulpiride tablet and at 5.0 hr +/- 0.8 (S.D.) after Dogmatil fort tablet. The maximal serum concentrations were 506.1 ng/ml +/- 87.2 (S.D.) and 509.1 ng/ml +/- 101.9 (S.D.) for Sulpiride and Dogmatil fort, respectively. The half-life of Sulpiride in serum was 9.9 hr +/- 1.3 (S.D.) following dosing with Dogmatil fort tablet and 12.2 hr +/- 3.0 (S.D.) following dosing with Sulpiride tablet.
Adult↗
Metabolism of levorotary 4,5-dihydrodiazepam in the rat.
The metabolism of (-)-4,5-dihydrodiazepam (7-chloro-1,3,4,5-tetrahydro-1-methyl-5-phenyl-2H-1,4-benzo[2-14C]diazepin-2-one) (I) was investigated in rats. Metabolites from urine and bile extracts purified by thin-layer chromatography were identified by mass spectrometry. Diazepam and its main metabolites were found among the biotransformation products of I. Based on these findings, the most important identified metabolic route of the compound studied appears to be the formation of an unsaturated bond between the N4 and C5 atoms, and further transformation of the diazepam formed.
Animals↗
Pharmacokinetics of apovincaminic acid in dogs.
After the oral or intravenous administration of 10 mg vinpocetine to dogs the pharmacokinetics of its main metabolite, apovincaminic acid (AVA) can be described by a two-compartment open model. The apparent half-life of its formation was 0.56 +/- 0.23 h and that of the apparent elimination was 9.6 h which did not significantly differ from the elimination half-life of total radioactivity (8.16 +/- 1.77 h) and from the apparent elimination half-life of vinpocetine itself (8.9 +/- 2.87 h). The volume of distribution of AVA was 2.3 times lower than that of vinpocetine and its clearance value (1.5 +/- 0.77 1 h-1 kg-1) was 2.8 times less than that of vinpocetine. These results suggest that AVA does not undergo further metabolism and its elimination is formation limited.
Administration, Oral↗
Pharmacokinetic and metabolic studies of vinpocetine on dogs. I. Pharmacokinetics.
The pharmacokinetics of tritiated vinpocetine has been studied on dogs. The drug, when administered orally, was readily absorbed from the gastrointestinal tract (T1/2 0.3 h) and underwent similarly fast distribution (T1/2 0.8 h) in the organism. The mean value of the elimination half-life was 8.2 h. Approx. 75% of the administered radioactivity was excreted with urine and feces within 72 h. The pharmacokinetics of the intravenously administered, labelled compound showed that a similarly rapid distribution but a somewhat slower elimination took place. Fecal and urinary excretion of radioactivity applied amounted to about 82%. Investigation of the distribution of radioactivity between plasma and blood cells revealed that the radioactivity content did not bind to the cellular fraction of the blood. Pharmacokinetic studies of the same design in the literature allowed us to make some comparison between dogs, rats and humans in respect to the kinetic behavior of labelled vinpocetine.
Animals↗
Pharmacokinetic and metabolic studies of vinpocetine on dogs. II. Metabolism.
Metabolic studies of vinpocetine were carried out by analysing the excreta of dogs treated orally or intravenously with the labelled compound. Our studies including various extraction procedures, TLC and MS structure identification revealed that vinpocetine underwent rapid and extensive metabolism in the animal organism. Unchanged parent drug was excreted via urine and feces only in a small or negligible portion. The prevailing metabolite in both urine and feces was apovincaminic acid. Two minor metabolites were also identified: hydroxy-vinpocetine and dihydroxy-apovincaminic acid-glycine amide. Beside the chemical structures and relative abundances of metabolites found in dogs, qualitative data referring to the metabolites occurring in the feces of orally treated humans, are also presented.
Administration, Oral↗