DIFFERENCES IN THE STEREOSELECTIVE PHARMACOKINETICS OF PAZINACLONE (DN-2327), A NEW ANXIOLYTIC, AND ITS ACTIVE METABOLITE AFTER INTRAVENOUSAND ORAL SINGLE DOSES TO DOGS

The stereoselective pharmacokinetics of the new nonbenzodiazepine anxi olytic 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 1 hr -1 kg-1. The total clearance and volumes of distribution (V(c), V(beta ), and V(ss)) of (S)-pazinaclone were significantly lower than those o f the antipode. The differences in disposition were consistent with st ereoselectivity 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 comp arable elimination half-lives for the two enantiomers. As projected fr om the intravenous results, the first-pass metabolism of (S)- and (R)- pazinaclone on oral administration of racemic pazinaclone was very ext ensive and stereoselective, with mean bioavailabilities Of 6.0 and 1.2 %, respectively, but the rates of absorption of the enantiomers were s imilar. Simultaneous model-dependent analysis of the intravenous plasm a profiles for parent drug and metabolite suggested stereoselectivity of the active metabolite M(II) with shorter formation half-life for (S )-M(II). However, in vitro metabolism by liver slices and our in vivo data indicated exclusive elimination of (S)- and (R)-pazinaclone throu gh complete conversion to the M(II) metabolite (f(m) = 1). Thus, the c learances of (S)- and (R)-M(II) were calculated to be 0.89 and 7.89 1 hr-1 kg-1, respectively, indicating pronounced stereoselectivity in th e metabolite clearance. The parallel decline in plasma profiles of par ent drug and the metabolite indicates that elimination of either (S)- or (R)-M(II) is rate-limited by its formation. Indeed, the model-depen dent analysis revealed the true elimination half-lives of (S)- and (R) -MN to be similar to each other but shorter than those of (S)- and (R) -pazinaclone.