STEREOSELECTIVE PHARMACOKINETICS OF PAZINACLONE, A NEW NONBENZODIAZEPINE ANXIOLYTIC, AND ITS ACTIVE METABOLITE IN HEALTHY-SUBJECTS

1 Serum and urine concentrations of enantiomers of pazinaclone (DN-2327) and an active metabolite M(II), were measured after single and twice daily oral doses of 4 and 8 mg racemic drug to healthy subjects. 2 The kinetics of rac-pazinaclone and rac-M(II) were dose-independent and no unchanged drug was recovered in urine. 3 The terminal elimination half-lives of the drug isomers were similar (about 10.5 h), but mean steady-state values of AUC were twofold higher for the S-isomer than those of the antipode (e.g., 8 mg dose: 127 vs 69 ng ml-1 h). However, the corresponding AUC values based upon unbound drug were similar (5.71 vs 5.73 ng ml-1 h) indicating no stereoselectivity in intrinsic metabolic clearance. 4 The terminal elimination half-lives of S- and R-M(II) were similar to those of parent compound indicating that the elimination of these metabolites is formation rate-limited. 5 The R:S-ratio for the AUCs of M(II) was 4: 1. Both enantiomers were excreted in the urine mainly as glucuronide conjugates, with stereoselectivity toward S-M(II). 6 Since only the S-enantiomers of DN-2327 and M(II) bind to the benzodiazepine receptor, further measurements of drug effect in patients should be related to combine serum concentrations of the S-enantiomers of both parent drug and M(II).