Enantioselective pharmacokinetics in animals of pazinaclone, a new isoindoline anxiolytic, and its active metabolite

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 (CL u ) of ( S )‐pazinaclone was, however, greater than that of the antipode in rats and dogs and the CL u 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.