Biomedical subjects
Publications and source records attributed to E Kvasnicková.
On incubation with the postmitochondrial fraction of the liver homogenate of rabbits, guinea-pigs, rats, and mice in the presence of NADPH and oxygen, the alpha-sympathomimetic trans-3-(2-hydroxyethylamino)-5,8-dimethoxy-1,2,3,4-tetrahydro-2-n aphthol (Tetraminol, 1) is preferentially O-demethylated in position 8, yielding metabolite 3. In male rats O-demethylation is stronger than in females.
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Female Wistar rats were pretreated with I ml of carbon tetrachloride/kg of body weight or with olive oil. All the rats were given this dose of CCl4 20 or 40 days later. Liver regeneration as evaluated by 3H-thymidine incorporation into liver DNA and by the number of mitotic hepatocytes was markedly impaired in CCl4-pretreated rats when compared with olive oil-pretreated controls. DNA labelling reached only 83 and 59% and mitotic index 35 and 58% of control values, respectively, at 20-day and 40-day time intervals. The variables characteristic of liver damage did not parallel the changes in cell division. About 20% of hepatocytes were necrotic both in the CCl4-pretreated and in the control rats. The activity of serum alanine aminotransferase was higher in the CCl4-pretreated rats. Only serum aspartate aminotransferase activities were somewhat lower when compared to controls. Similarly, serum aminotransferases were much less affected by the pretreatment than the markers of regeneration when two low doses of CCl4 (0.125 ml/kg) were given to rats 20 days apart. The activities of microsomal enzymes aniline hydroxylase and pethidine demethylase were equal in control and in experimental rats 20 days after CCl4 pretreatment which indicated that the effects of CCl4 were not mediated by an overall decrease in cytochrome P-450 enzymes. In summary, a single pretreatment of rats with CCl4 induced changes in liver that lasted for 40 days and impaired liver regeneration when another dose of CCl4 was applied.
The study of the biotransformation of the potential cytostatic benfluron has been continued. The elimination of benfluron and of nine of its metabolites whose structure had been established, mainly on the basis of the comparison of their IR, MS and NMR spectra with those of standards, was studied. After oral administration of 500 mg.kg-1 to rats, the amounts of these substances in the faeces and urine were followed up by high-performance liquid chromatography for five days. Striking qualitative and quantitative differences were observed in the elimination of benfluron and its metabolites by both routes.
The results produced by a new method of calculation based on the knowledge of the absorption coefficient and instrumental parameters without the concomitant use of a standard were compared with those calculated by the routine external standard method for a model system utilizing the quantification of benzofluorene derivatives. These were present in the incubation mixture of 5-[2-(dimethylamino)ethoxy]-7-oxo-7H-benzo[c]fluorene (benflurone) with the microsomal fraction of rat liver homogenate. Reasonable agreement between the two methods was observed. The potential utility of the new method of calculation is discussed.
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Detection reactions and RF values in thin-layer chromatography on silica gel were studied for the antineoplastic drug Ih (benfluron) and related substances. On incubation of Ih with homogenate fractions of mammalian livers the N-oxide Ii and 5-[2-(N,N-dimethylamino)ethoxy]-7-hydroxy-7 H-benzo[c]fluorene (IIh) were established as products, and 5-[2-(N-methylamino)ethoxy]-7-oxo-7 H-benzo[c]fluorene (Ig), 5-[2-(N-methylamino)ethoxy]-7-hydroxy-7 H-benzo[c]fluorene (IIg) and a phenolic product of benfluron (IV) were tentatively identified.
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