Stereoselective pharmacokinetics of pazinaclone, a new non-benzodiazepine anxiolytic, and its active metabolite in healthy subjects.
1. Serum and urine concentrations of enantiomers of pazinaclone (DN-2327) and an active metabolite MII, 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-MII 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-MII 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 MII was 4:1. Both enantiomers were excreted in the urine mainly as glucuronide conjugates, with stereoselectivity toward S-MII. 6. Since only the S-enantiomers of DN-2327 and MII 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 MII.
Hussein
Z
Z
Drug Metabolism Division, Pharmaceutical Products Research and Development, Abbott Laboratories, Abbott Park, Illinois, USA.
Mulford
D J
DJ
Bopp
B A
BA
Granneman
G R
GR
D000284:Administration, Oral; D000328:Adult; D014151:Anti-Anxiety Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001569:Benzodiazepines; D006207:Half-Life; D006801:Humans; D054833:Isoindoles; D008297:Male; D009287:Naphthyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013141:Spiro Compounds / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013237:Stereoisomerism; D013607:Tablets
D014151:Anti-Anxiety Agents; D054833:Isoindoles; D009287:Naphthyridines; D013141:Spiro Compounds; D013607:Tablets; D001569:Benzodiazepines; C060382:pazinaclone