摘要：5-[(2-Aminoacetamido) methyl]-1-[p-chloro-2-(o-chlorobenzoyl) phenyl]-N, N-dimethyl-1 H-1, 2, 4-triazole-3-carboxamide hydrochloride dihydrate (450191-S), a sleep inducer, is a ring-opened derivative of 1, 4-benzodiazepine and has been reported to be activated by intestinal aminopeptidases in a step of absorption. In this study, we investigated the role of the intestinal aminopeptidases in the uptake of 450191-S by the intestine by using various aminopeptidase inhibitors in everted sacs of rat small intestine in vitro. Glycylglycine did not affect the desglycylation of 450191-S but glycyl-L-leucine or L-leucyl-L-leucine inhibited the reaction. This inhibition was accompanied by reduced concentration of 450191-S metabolites in the intestinal tissue. When the incubation was carried out at 0°C or with puromycin, the desglycylation was also inhibited and the concentration was similarly reduced. Since the extent of inhibition of the desglycylation of 450191-S was negatively correlated with the total concentration of 450191-S metabolites in the intestinal tissue (r=-0.9660), the aminopeptidases must play an important role in the uptake of 450191-S by the intestine. To confirm this, we examined the uptake of the desglycylated product of 450191-S, 8-chloro-6-(2-chlorophenyl)-N, N-dimethyl-4H-1, 2, 4-triazolo-[1, 5-α] [1, 4]-benzodiazepine-2-carboxamide (M-1) in the same manner. No effect of dipeptides, puromycin or reduced temperature was found on M-1 uptake by the intestine, leading to the conclusion that the aminopeptidases are important for enhancing the uptake of 450191-S in the intestine.
