REDUCED SYSTEMIC AVAILABILITY OF AN ANTIARRHYTHMIC DRUG, BIDISOMIDE, WITH MEAL COADMINISTRATION - RELATIONSHIP WITH REGION-DEPENDENT INTESTINAL-ABSORPTION

Purpose. The aim of this research was to determine the mechanism by wh ich 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 subje cts. A dialysis technique was employed to examine the potential for dr ug binding to meal homogenates. Plasma levels, following drug administ ration through duodenal and jejunal intestinal access ports and follow ing various meal treatments with oral drug co-administration, were com pared for bidisomide and disopyramide in a canine model. Results. Bidi somide plasma AUC was significantly reduced following oral drug co-adm inistration with breakfast compared to fasted-state controls in human subjects and in dogs independent of the composition of the solid cooke d breakfast. While intravenous bidisomide infusion in human subjects s howed a statistically significant reduction in AUC 15 minutes after or al administration of a high fat breakfast as compared to drug infusion in the fasted state, the reduction (-13%) was substantially smaller t han the reduction (from -43% to -63%) observed with oral bidisomide me al co-administration. The percentages of bidisomide and disopyramide l ost by binding to homogenates of cooked breakfast were 25.0 +/- 5.7% a nd 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 bidi somide absorption from mid-jejunal administration was significantly lo wer than for oral or duodenal administration. Non-viscous liquid meals decreased C-max but not AUG, while viscous homogenized solid meals de creased both C-max and AUC for bidisomide with oral drug-meal co-admin istration. Oral non-caloric hydroxypropyl methylcellulose meals decrea sed bidisomide to the same extent as homogenized solid meals but did n ot lower disopyramide AUC. Conclusions. The significant reduction in b idisomide plasma levels observed with meal co-administration in human subjects was predominantly mediated through a reduction in drug absorp tion and was independent of solid meal composition. The difference in meal effect on the absorption of the two drugs in humans did not appea r to be a function of drug binding to cooked meal components over typi cal human upper gastrointestinal residence times. In dogs, the high-vi scosity medium generated by oral co-administration of a solid meal red uced the upper intestinal absorption of bidisomide and disopyramide. B idisomide AUC was decreased since it was well absorbed in the upper bu t not lower small intestine. Disopyramide AUC was not significantly af fected since it was well absorbed from both regions. A similar mechani sm may play a role in drug plasma level reductions following oral co-a dministration with solid meals for drugs showing similar regionally-de pendent absorption profiles.