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  • Title: Stereoselective pharmacokinetics of pazinaclone, a new non-benzodiazepine anxiolytic, and its active metabolite in healthy subjects.
    Author: Hussein Z, Mulford DJ, Bopp BA, Granneman GR.
    Journal: Br J Clin Pharmacol; 1993 Oct; 36(4):357-61. PubMed ID: 12959315.
    Abstract:
    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.
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