CCK antagonist pre-treatment inhibits meal-enhanced drug absorption in dogs.
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, 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.
Miles
C
C
College of Pharmacy, University of Michigan, Ann Arbor 48109-1065, USA.
Dickson
P
P
Rana
K
K
Lippert
C
C
Fleisher
D
D
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D020109:Devazepide; D004285:Dogs; D004386:Duodenum / Q000378:metabolism; D004435:Eating; D005217:Fat Emulsions, Intravenous / Q000008:administration & dosage; D005500:Follow-Up Studies; D005704:Gallbladder / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects*; D019301:Oleic Acid / Q000378:metabolism; D010672:Phenytoin / Q000493:pharmacokinetics*
D001570:Benzodiazepinones; D005217:Fat Emulsions, Intravenous; D006727:Hormone Antagonists; D019301:Oleic Acid; D010672:Phenytoin; D002766:Cholecystokinin; D020109:Devazepide