title: Enantioselective pharmacokinetics in animals of pazinaclone, a new isoindoline anxiolytic, and its active metabolite.
abstract: The enantioselective pharmacokinetics of a new anxiolytic, pazinaclone (DN-2327), and its active metabolite, M-II, were studied in animals. In rats and dogs given racemic pazinaclone intravenously, the total clearance and volume of distribution of (S)-pazinaclone were lower than those of (R)-pazinaclone, whereas the opposite results were obtained in monkeys. The differences in disposition were consistent with enantioselective protein binding, where the unbound fraction was greater for (R)-pazinaclone than that for the (S)-enantiomer in rats and dogs; the reverse was noted in monkeys. Lower clearance and distribution for (S)-pazinaclone in rats and dogs, and for the (R)-enantiomer in monkeys, resulted in comparable plasma profiles for the pazinaclone enantiomers and thereby those of the corresponding enantiomers of M-II. The unbound clearance (CLu) of (S)-pazinaclone was, however, greater than that of the antipode in rats and dogs and the CLu of each enantiomer was similar in monkeys. Thus, enantioselectivity in the kinetics of (S)- and (R)-pazinaclone appears to reside largely in plasma binding differences and is unrelated to variations in intrinsic clearance. The first-pass metabolism of (S)- and (R)-pazinaclone on oral administration of the racemate was enantioselective, with respective bioavailabilities of 1.7 and 0.8% in rats, 10.4 and 1.9% in dogs, and 0 and 11.4% in monkeys. Therefore, the enantioselectivity was more pronounced after oral dosing.
authors.affiliation: Drug Analysis and Pharmacokinetics Research Laboratories, Takeda Chemical Industries Ltd., Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kondo
authors.forename: K
authors.initials: K
authors.lastname: Yoshida
authors.forename: Y
authors.initials: Y
authors.lastname: Yoshimura
authors.forename: S
authors.initials: S
authors.lastname: Tanayama
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004285:Dogs; D004912:Erythrocytes / Q000378:metabolism; D007275:Injections, Intravenous; D054833:Isoindoles; D008252:Macaca fascicularis; D008297:Male; D009287:Naphthyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013141:Spiro Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013237:Stereoisomerism; D014018:Tissue Distribution
chemical_list: D014151:Anti-Anxiety Agents; D001798:Blood Proteins; D054833:Isoindoles; D009287:Naphthyridines; D013141:Spiro Compounds; C060382:pazinaclone