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  • 1
    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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  • 2
    Electronic Resource
    Electronic Resource
    Reduced Systemic Availability of an Antiarrhythmic Drug, Bidisomide, with Meal Co-administration: Relationship with Region-Dependent Intestinal Absorption (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 221-227 
    Details
    ISSN: 1573-904X
    Keywords: drug absorption ; food effects ; site-specific absorption ; regional-dependent absorption ; intestinal clearance ; viscosity ; bidisomide ; disopyramide ; canine model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The aim of this research was to determine the mechanism by which a co-administered meal decreases the oral absorption of bidisomide and does not influence the oral absorption of the chemically-related antiarrhythmic agent, disopyramide. Methods. Bidisomide plasma levels, following oral administration and intravenous infusion in the fasted state and with various meal treatments, were determined in human subjects. A dialysis technique was employed to examine the potential for drug binding to meal homogenates. Plasma levels, following drug administration through duodenal and jejunal intestinal access ports and following various meal treatments with oral drug co-administration, were compared for bidisomide and disopyramide in a canine model. Results. Bidisomide plasma AUC was significantly reduced following oral drug co-administration with breakfast compared to fasted-state controls in human subjects and in dogs independent of the composition of the solid cooked breakfast. While intravenous bidisomide infusion in human subjects showed a statistically significant reduction in AUC 15 minutes after oral administration of a high fat breakfast as compared to drug infusion in the fasted state, the reduction (−13%) was substantially smaller than the reduction (from −43% to −63%) observed with oral bidisomide meal co-administration. The percentages of bidisomide and disopyramide lost by binding to homogenates of cooked breakfast were 25.0 ± 5.7% and 23.7 ± 7.7%, respectively, as determined by dialysis at 4 hours. In dogs, the extent of absorption of disopyramide was comparable from oral, duodenal and mid-jejunal administration while the extent of bidisomide absorption from mid-jejunal administration was significantly lower than for oral or duodenal administration. Non-viscous liquid meals decreased Cmax but not AUC, while viscous homogenized solid meals decreased both Cmax and AUC for bidisomide with oral drug-meal co-administration. Oral non-caloric hydroxypropyl methylcellulose meals decreased bidisomide to the same extent as homogenized solid meals but did not lower disopyramide AUC. Conclusions. The significant reduction in bidisomide plasma levels observed with meal co-administration in human subjects was predominantly mediated through a reduction in drug absorption and was independent of solid meal composition. The difference in meal effect on the absorption of the two drugs in humans did not appear to be a function of drug binding to cooked meal components over typical human upper gastrointestinal residence times. In dogs, the high-viscosity medium generated by oral co-administration of a solid meal reduced the upper intestinal absorption of bidisomide and disopyramide. Bidisomide AUC was decreased since it was well absorbed in the upper but not lower small intestine. Disopyramide AUC was not significantly affected since it was well absorbed from both regions. A similar mechanism may play a role in drug plasma level reductions following oral co-administration with solid meals for drugs showing similar regionally-dependent absorption profiles.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011958400362
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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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