CCK antagonist pre-treatment inhibits meal-enhanced drug absorption in dogs

Abstract

Duodenal administration of casein and oleate increased plasma levels from oral administration of a poorly water-soluble antiepileptic drug as compared to duodenal glucose and saline in a canine model. Pre-treatment with intravenous MK-329, a benzodiazepine CCK A-receptor antagonist, blocked the duodenal oleate effect on drug plasma levels in a single dog preliminary study. In a follow-up study, oral drug co-administration with Intralipid increased drug plasma levels as compared to drug co-administration with a noncaloric equivalent-volume load in seven dogs. Pre-treatment with MK-329 reduced drug plasma levels from co-administration with Intralipid toward fasted-state values. While increased drug solubility in the lipid vehicle might have been projected to account for the fed-state effect in the oral studies, the gut peptide inhibitor studies suggest that biliary secretion plays a major role in promoting the dissolution and subsequent absorption of this lipophilic drug. The data also support the hypothesis that meal-enhanced pancreatic secretion provides a greater fluid volume for drug dissolution in the small intestine. An increase in the extent of drug dissolution in the stomach, as a result of meal prolongation of gastric residence time, does not appear to contribute substantially to fed-state increases in drug plasma levels from oral drug co-administration with a lipid meal.