Mechanisms of food effects of structurally related antiarrhythmic drugs, disopyramide and bidisomide in the rat.
OBJECTIVE
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.
Lee
K H
KH
G. D. Searle & Co., Skokie, Illinois 60077, USA.
Xu
G X
GX
Schoenhard
G L
GL
Cook
C S
CS
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D004206:Disopyramide / Q000493:pharmacokinetics*; D005215:Fasting; D018565:Food-Drug Interactions; D005772:Gastrointestinal Transit / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007082:Ileum / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects; D007583:Jejunum / Q000378:metabolism; D008297:Male; D010539:Permeability; D010880:Piperidines / Q000493:pharmacokinetics*; D051381:Rats; D012965:Sodium Chloride / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D010880:Piperidines; C061991:bidisomide; D012965:Sodium Chloride; D004206:Disopyramide