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Enantioselective pharmacokinetics in animals of pazinaclone, a new isoindoline anxiolytic, and its active metabolite
Author(s) -
Kondo Takahiro,
Yoshida Kiyoshi,
Yoshimura Yoshinobu,
Tanayama Shigeharu
Publication year - 1995
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2510160906
Subject(s) - pharmacokinetics , enantiomer , anxiolytic , chemistry , volume of distribution , enantioselective synthesis , metabolite , pharmacology , oral administration , isoindoline , metabolism , active metabolite , stereochemistry , biochemistry , receptor , biology , catalysis , organic chemistry
Abstract 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.