Differences in the stereoselective pharmacokinetics of pazinaclone (DN-2327), a new anxiolytic, and its active metabolite after intravenous and oral single doses to dogs.

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)