title: Differences in the stereoselective pharmacokinetics of pazinaclone (DN-2327), a new anxiolytic, and its active metabolite after intravenous and oral single doses to dogs.
abstract: The stereoselective pharmacokinetics of the new nonbenzodiazepine anxiolytic compound pazinaclone (DN-2327) were studied in four beagle dogs after oral (2.5 mg/kg) and intravenous (0.5 mg/kg) administration of racemate in a two-way, crossover study design. Racemic pazinaclone was highly cleared after intravenous administration at 2.09 +/- 0.78 l hr-1 kg-1. The total clearance and volumes of distribution (Vc, V beta, and Vss) of (S)-pazinaclone were significantly lower than those of the antipode. The differences in disposition were consistent with stereoselectivity in protein binding, where the unbound fraction of (R)-pazinaclone was almost 5-fold greater than that of the (S)-enantiomer. Lower clearance and distribution for (S)-pazinaclone resulted in comparable elimination half-lives for the two enantiomers. As projected from the intravenous results, the firstpass metabolism of (S)- and (R)-pazinaclone on oral administration of racemic pazinaclone was very extensive and stereoselective, with mean bioavailabilities of 6.0 and 1.2%, respectively, but the rates of absorption of the enantiomers were similar. Simultaneous model-dependent analysis of the intravenous plasma profiles for parent drug and metabolite suggested stereoselectivity of the active metabolite MII with shorter formation half-life for (S)-MII. However, in vitro metabolism by liver slices and our in vivo data indicated exclusive elimination of (S)- and (R)-pazinaclone through complete conversion to the MII metabolite (fm = 1). Thus, the clearances of (S)- and (R)-MII were calculated to be 0.89 and 7.89 l hr-1 kg-1, respectively, indicating pronounced stereoselectivity in the metabolite clearance.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Drug Metabolism Division, Abbott Laboratories, Abbott Park, IL 60064.
authors.forename: Z
authors.initials: Z
authors.lastname: Hussein
authors.forename: D J
authors.initials: DJ
authors.lastname: Mulford
authors.forename: B A
authors.initials: BA
authors.lastname: Bopp
authors.forename: G R
authors.initials: GR
authors.lastname: Granneman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism; D002250:Carbon Radioisotopes; D004285:Dogs; D007275:Injections, Intravenous; D054833:Isoindoles; D008297:Male; D009287:Naphthyridines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding; D013141:Spiro Compounds / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D013237:Stereoisomerism
chemical_list: D014151:Anti-Anxiety Agents; D001798:Blood Proteins; D002250:Carbon Radioisotopes; D054833:Isoindoles; D009287:Naphthyridines; D013141:Spiro Compounds; C060382:pazinaclone