DISPOSITION OF DN-2327, A NEW ANXIOLYTIC, IN RATS, DOGS, AND MONKEYS

The disposition of DN-2327 after oral dosing of C-14-labeled DIV-2327 ([C-14]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 0.002 mu g/ml), then declined, with a half-life (t(1/2)) of 3 h. T-max, C-max and t(1/2) of DN-2327 in dogs and monkeys were 0.6 h, 0.332 mu g/ml and 1.5 h, and 2.3 h, 0.036 mu g/ml and 6.2 h, 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 [C-14]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 mag depend largely on M-II. In these animals, [C-14]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.