Bioavailability of avitriptan was found to decrease significantly when administered 5 min after a standard high fat meal. The studies described herein were carried out to gain insight into the mechanism of this food effect. A series of studies were conducted in humans to assess the effect of timing of meal, type of meal, gastric pH, change in the formulation and dose on the bioavailability of avitriptan. Avitriptan was administered as a 50 mg capsule under fasted condition and at 30 min, 1 , 2 and 4 h after a standard high fat meal. The reduction in avitriptan bioavailability persisted even at 4 h post high fat meal, although as the time interval between the meal and dose increased, the effect of meal tended to decrease. Bioavailability of avitriptan also decreased significantly when the drug was administered after a high protein and a high carbohydrate meal. Elevation in gastric pH caused by food was not found to be responsible for the food-related decrease in bioavailability of avitriptan since ranitidine pretreatment did not lead to a decrease in bioavailability. When administered as a 50 mg 14 C-labeled solution after a standard high fat meal, bioavailability of avitriptan decreased although the decrease was less compared with that observed for a capsule dosage form. Plasma concentrations and cumulative urinary excretion of total radioactivity also decreased in the fed condition, indicating the absorption of avitriptan was affected. The decrease in avitriptan AUC was somewhat more pronounced than the decrease in the exposure to the total radioactivity suggesting a food-related increase in the first-pass metabolism of avitriptan. Effect of the standard high fat meal on avitriptan administered as a 150 mg capsule was similar to that observed at the 50 mg dose. Overall, the results indicate that bioavailability of avitriptan is significantly reduced irrespective of the type of meal, dose and dosage form and the effect persists for as long as 4 h post meal. Thus, it appears that avitriptan absorption and bioavailability are highly sensitive to presence of food in the stomach and any food-related changes in gastric emptying time and gastrointestinal motility.