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.