EFFECT OF FOOD ON ABSORPTION OF 450191-S, A 1H-1,2,4-TRIAZOLYL BENZOPHENONE DERIVATIVE FROM RAT SMALL INTESTINE

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5-[(2-Aminoacetamide) methyl]-1-[p-chloro-2-(o-chlorobenzoyl) phenyl]-N, N-dimethyl-1H-s-triazole-3-carboxamide hydrochloride dihydrate (450191-S), a newly synthesized sleep inducer, is a masked compound which is converted to 1,4-benzodiazepine by intestinal aminopeptidases during absorption from the small intestine. This study was an investigation on the effects of food on 450191-S pharmacokinetics. When ^<14>C-450191-S was administered to non-fasted rats, peak plasma levels of total radioactivity were markedly reduced and its excretion into the bile was more delayed than when it was administered to fasted rats. One of the causes for these phenomena was thought to be a delayed absorption caused by the direct interaction between 450191-S and food in the intestinal lumen as well as the delayed gastric emptying rate. To confirm this interaction, we examined the effect of food on 450191-S uptake by the small intestine using rat everted jejunal sac in vitro. Subsequently, we found that the desglycylation of 450191-S was inhibited by rat food and that the uptake of 450191-S was reduced. In conclusion, 450191-S absorption is delayed by food, which results in the decreased total plasmal level of 450191-S metabolites.
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