Effect of food on the absorption of drugs: Relationship with site-specific absorption in dogs.

Abstract

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. 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. 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 in dogs. Non-viscous liquid meals decreased C$\rm\sb{max}$ but not AUC, while viscous homogenized solid meals decreased both C$\rm\sb{max}$ and AUC for bidisomide with oral drug-meal co-administration. Non-caloric hydroxypropyl methylcellulose meals significantly decreased bidisomide but not disopyramide AUC from oral administration. The high-viscosity medium generated by oral co-administration of a solid meal reduces the upper intestinal absorption of bidisomide and disopyramide in dogs. Bidisomide AUC is decreased since it is well absorbed in the upper but not lower small intestine. Disopyramide AUC is not significantly affected since it is well absorbed from both regions. The primary contribution of this research is that a mechanistic relationship between site-specific absorption and negative food effects on drug absorption has been isolated. A similar mechanism may play a role in drug plasma level reductions following oral co-administration with solid meals for drugs showing similar site-dependent absorption profiles.