Mechanism of compound- and species-specific food effects of structurally related antiarrhythmic drugs, disopyramide and bidisomide.
OBJECTIVE
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.
Cook
C S
CS
G. D. Searle & Co., Skokie, Illinois 60077, USA. CSCOOK@SEARLE.MONSATO.COM
Zhang
L
L
Osis
J
J
Schoenhard
G L
GL
Karim
A
A
D000328:Adult; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D004041:Dietary Fats / Q000008:administration & dosage* / Q000097:blood; D004206:Disopyramide / Q000097:blood / Q000493:pharmacokinetics*; D004285:Dogs; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D007408:Intestinal Absorption; D008099:Liver / Q000378:metabolism; D008297:Male; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics*; D013045:Species Specificity; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D004041:Dietary Fats; D010880:Piperidines; C061991:bidisomide; D004206:Disopyramide