Enantiomeric toxicokinetics of the new isoindoline anxiolytic pazinaclone in rats and dogs

Enantiomeric toxicokinetics of the new isoindoline pazinaclone (GAS 103255-66-9, DN-2327) were studied in rats and dogs of both sexes after oral administration by gavage. Non-toxic doses in 4-week toxicity studies in rats are greater than or equal to 3000 mg/kg/d and 500 mg/kg/d for S- and R-pazinaclone, respectively; the corresponding doses in dogs are 10 and 4 mg/kg/d, respectively. R-Pazinaclone is more toxic in female rats than in male rats. In both rats and dogs, circulating enantiomer concentrations of pazinaclone and the active M-II metabolite increased with dose. Higher S- and R-pazinaclone concentrations were found in female rats than in male rats; the concentrations in dogs were sex independent. In rats, the AUCs for the parent compound after a 3000 mg/kg oral dose of S-pazinaclone were about 9-fold (males) and 4-fold (females) greater than those after dosing of R-pazinaclone at 500 mg/kg. In dogs, the AUC for the parent compound after a 10 mg/kg oral dose of S-pazinaclone was 33-fold greater than that after oral dosing of the R-enantiomer at 4 mg/kg. The toxic activity is thus likely to reside predominantly in the R-enantiomers of pazinaclone and M-II. The exposure of the R-enantiomers in humans, after administration of the anticipated clinical dose of the racemic drug, seemed to be no more than that in rats and dogs at nontoxic doses.