Clozapine pharmacokinetics and pharmacodynamics studied with CYP1A2-null mice

The aim of this study was to use the CYP1A2-null mouse to investigate the i n-vivo contribution of CYP1A2 to clozapine pharmacokinetics and pharmacodyn amics. An intraperitoneal injection of 10 mg/kg clozapine was administered to four male CYP1A2 -/- mice and four male wild-type mice. Clozapine, desme thylclozapine, and clozapine N-oxide concentrations in sequential tail bloo d samples were measured by HPLC with UV detection. Behavioural parameters w ere recorded at each time point. The area under the curve (AUC) of clozapin e was 2.6 times greater, the clearance of clozapine was 2.6 times slower, a nd the half-life was 1.2 times longer in the CYP1A2 -/- mice (p = 0.0143) a s compared to the wild-type mice. Sixty-one percent of the clozapine cleara nce in wild-type mice was calculated to be mediated by CYP1A2, The AUC of d esmethylclozapine was 1.6 times lower in the CYP1A2 -/- mice compared to th e wild-type mice (p = 0.0286), while there was a trend for the AUC of cloza pine N-oxide to be greater in the CYP1A2 -/- mice (p = 0.0571). The CYP1A2 -/- mice were significantly more drowsy and showed more motor impairment (p = 0.0145) and myoclonus than the wild-type mice. Our results indicate that , in vivo, CYP1A2 is the major determinant of clozapine clearance, contribu tes significantly to the demethylation of clozapine, and has a negligible c ontribution to the N-oxidation, Our data also indicate that CYP1A2 poor met abolizers might be more susceptible than extensive metabolizers to dose-rel ated adverse effects of clozapine, such as sedation, myoclonus and seizures .