Disposition of DN-2327,a New Anxiolytic, in Rats, Dogs, and Monkeys

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The disposition of DN-2327 after oral dosing of ^<14>C-labeled DN-2327 ([^<14>C]DN-2327) to rats, dogs and monkeys was studied. DN-2327 was absorbed from the small intestine after oral administration. In the plasma of these animals, a small amount of unchanged compound and M-I were detected, with M-II (a pharmacologically active metabolite) as a major component. The concentration of the unchanged compound in rat plasma attained a peak (C_<max>0.002μg/ml), then declined, with a half-life (t_<1/2>) of 3 h. T_<tax>, C_<max> and t_<1/2> of DN-2327 in dogs and monkeys were 0.6 h, 0.332μg/ml and 1.5h, and 2.3h, 0.036μg/ml and 6.2h, respectively. About 60,75 and 48% of the radioactivity dosed was absorbed in rats, dogs and monkeys, respectively, whereas the bioavailability in rats, dogs and monkeys was less than 1,34 and 10%, respectively, indicating that DN-2327 had been subjected to the first pass effect. In rats given [^<14>C] DN-2327 orally, the radioactivity was distributed widely in various tissues, including the brain. In the brain regions, DN-2327 and M-II were distributed and M-II was major component, indicating that the pharmacological effects of DN-2327 may depend largely on M-II. In these animals, [^<14>C] DN-2327 was excreted in feces via bile mostly as metabolites. During repeated oral administration, DN-2327 and its metabolites did not accumulate in rat tissues, except in the kidney.
公益社団法人日本薬学会の論文
1995-02-15