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  • Electronic Resource  (3)
  • 1995-1999  (3)
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  • Electronic Resource  (3)
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  • 1
    Electronic Resource
    Electronic Resource
    Species Dependent Esterase Activities for Hydrolysis of an Anti-HIV Prodrug Glycovir and Bioavailability of Active SC-48334 (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1158-1164 
    Details
    ISSN: 1573-904X
    Keywords: glycovir ; SC-48334 ; esterase activities ; species difference ; in vitro-in vivo correlation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The in vitro fate of an ester prodrug, glycovir, was studied to determine if the species differences in the bioavailability of pharmacologically active SC-48334 observed after glycovir administration and not observed after SC-48334 administration is due to species differences in ester hydrolysis rate or species differences in absorption of the prodrug itself, and to determine the site(s) of ester hydrolysis which contributes most to species differences in the bioavailability of SC-48334 if any. Methods. Glycovir was incubated with small intestinal mucosa, liver S9 fractions, whole blood, red blood cells (RBC) and plasma of the rat, dog, monkey (cynomolgus and rhesus) and man, and glycovir concentrations were determined by HPLC. Results. The relative bioavailabilities of SC-48334 after prodrug administration to the rat, dog, monkey and man were 99,15, 42 and 37%, respectively. After SC-48334 administration, SC-48334 was rapidly and similarly well absorbed in all species. The hydrolysis rate in the small intestinal mucosa was well correlated with the relative bioavailability of SC-48334 after prodrug administration. Among different species the hydrolysis rate of glycovir in liver S9 fractions, blood, RBC and plasma did not parallel those in the mucosa of the small intestine. Conclusions. The species differences in bioavailability of SC-48334 with the prodrug were due to species differences in hydrolysis rates of the prodrug in small intestinal mucosa. The monkey was a good animal model for prediction of esterase activity in human small intestine and relative bioavailability in man.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016259826037
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Mechanisms of Food Effects of Structurally Related Antiarrhythmic Drugs, Disopyramide and Bidisomide in the Rat (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 1030-1038 
    Details
    ISSN: 1573-904X
    Keywords: food effect ; disopyramide ; bidisomide ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine whether the rat is a good animal model for the food effects observed with bidisomide but not with the structurally similar antiarrhythmic drug, disopyramide in man and to explore a reason for the differences in the food effects of these compounds. Methods. The following effects on the absorption of bidisomide and/ or disopyramide were examined in the rat: Food effects, gastrointestinal transit time under fasting and nonfasting conditions, pH effects, hypertonic solution effect of NaCl and glucose, bile effects, permeability, inhibitory effects by Gly, Gly-Gly, Gly-Pro, glucose and mannitol and drug binding to food. Results. Remarkable food effects were observed with bidisomide but not with disopyramide. There was no difference in the GI transit time with and without food. The pH effect with and without food was similar. Effect of salt concentrations on bidisomide and disopyramide was similar. There was no bile effect on absorption of both compounds. Binding of bidisomide and disopyramide to food was similarly low. The apparent permeability of bidisomide was much lower than disopyramide especially in the ileum and its absorption was more inhibited by Gly, Gly-Gly and Gly-Pro. Conclusions. In the rat, as previously seen in humans, the food effect was observed with bidisomide but not with disopyramide. This difference was in part due to both lower intestinal permeability of bidisomide compared to disopyramide and greater inhibition of absorption by the amino acid, Gly and the dipeptides, Gly-Gly and Gly-Pro.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1012101311826
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Mechanism of Compound- and Species-Specific Food Effects of Structurally Related Antiarrhythmic Drugs, Disopyramide and Bidisomide (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 429-433 
    Details
    ISSN: 1573-904X
    Keywords: food effect ; bidisomide ; disopyramide ; dog ; species difference
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine mechanism of food effects observed with bidisomide but not with the structurally similar drug, disopyramide. Methods. Food effect studies of bidisomide and disopyramide were conducted with and without a standardized high fat meal in healthy subjects and in the dog. Intestinal metabolism of disopyramide and absorption of the metabolites were examined after oral administration of the drug to the dogs with portal vein canula implanted. Effects of food or a mixture of amino acids on metabolism of [14C]disopyramide were examined after intraportal infusion of the drug with and without high fat meal and after drug infusion into portal vein with the amino acid mixture, respectively. Results. The systemic availability of bidisomide was markedly reduced with food in humans, whereas the systemic availability of disopyramide did not change notably. In the dog, the systemic availability of bidisomide was also reduced with food. The systemic availability of disopyramide did not change with food. This was due to the fact that reduction in absorption was compensated by reduction of metabolism. There was no evidence for reduction in hepatic and intestinal metabolism with food. Conclusions. The apparent reduction in disopyramide metabolism with food may be due to an increase in colonal and /or lymphatic absorption. Food effects on the apparent systemic availability of bidisomide and disopyramide in the dog were similar to those in the rat. However, there was substantial species difference in the mechanism of food effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011976331738
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    Paper (German National Licenses)
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