Disposition of DN-2327, a new anxiolytic, in rats, dogs, and monkeys.
The disposition of DN-2327 after oral dosing of 14C-labeled DN-2327 ([14C]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 (Cmax 0.002 microgram/ml), then declined, with a half-life (t1/2) of 3 h. Tmax, Cmax and t1/2 of DN-2327 in dogs and monkeys were 0.6 h, 0.332 microgram/ml and 1.5 h, and 2.3 h, 0.036 microgram/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 [14C]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, [14C]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.
Kondo
T
T
Drug Analysis and Pharmacokinetics Research Laboratories, Pharmaceutical Development Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Kurata
Y
Y
Yoshida
K
K
Yoshimura
Y
Y
D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004285:Dogs; D054833:Isoindoles; D008252:Macaca fascicularis; D008297:Male; D009287:Naphthyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013141:Spiro Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D014151:Anti-Anxiety Agents; D054833:Isoindoles; D009287:Naphthyridines; D013141:Spiro Compounds; C060382:pazinaclone