Clozapine pharmacokinetics and pharmacodynamics studied with CYP1A2-null mice

Abstract

The aim of this study was to use the CYP1A2-null mouse to investigate the in-vivo contribution of CYP1A2 to clozapine pharmacokinetics and pharmacodynamics. An intraperitoneal injection of 10 mg/kg clozapine was administered to four male CYP1A2 -/- mice and four male wild-type mice. Clozapine, desmethylclozapine, and clozapine N-oxide concentrations in sequential tail blood samples were measured by HPLC with UV detection. Behavioural parameters were recorded at each time point. The area under the curve (AUC) of clozapine was 2.6 times greater, the clearance of clozapine was 2.6 times slower, and the half-life was 1.2 times longer in the CYP1A2 -/- mice (p = 0.0143) as compared to the wild-type mice. Sixty-one percent of the clozapine clearance in wild-type mice was calculated to be mediated by CYP1A2. The AUC of desmethylclozapine was 1.6 times lower in the CYP1A2 -/- mice compared to the wild-type mice (p = 0.0286), while there was a trend for the AUC of clozapine 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, contributes significantly to the demethylation of clozapine, and has a negligible contribution to the N-oxidation. Our data also indicate that CYP1A2 poor metabolizers might be more susceptible than extensive metabolizers to dose-related adverse effects of clozapine, such as sedation, myoclonus and seizures.

Sleep Homeostatic and Waking Behavioral Phenotypes inEgr3-Deficient Mice Associated with Serotonin Receptor 5-HT2 Deficits

“…A washout period of 24 h or more was allowed between two consecutive treatments. The washout periods were more than 10 times the half-lives of clozapine (110 min 20 ) and the 5-HT2A antagonist MDL100907 (71 min 21 ) and exceeded the duration of previously reported EEG effects (5-HT2BC;SB206553: 3 h 14 ) by eightfold. The animals were treated in matched pairs of the same sex and body weight and opposite genotype.…”

Management of clozapine-resistant schizophrenia

“…Clozapine is also subject to considerable metabolism by the cytochrome P450 (CYP) enzyme system (Aitchison et al, 2000). There are numerous variants of the genes encoding the CYP enzyme family within the general population, resulting in complex individual genetic profiles and a variable response to drugs metabolised by these enzymes (Ma et al, 2004).…”

Pharmacogenetics and Psychiatry

“…From a pharmacokinetic point of view, it has been shown that CYP1A2 is the major determinant of clozapine clearance [4] (though CYP2C19, 2D6, 3A4, and 2C9 are also involved), and that there is wide interindividual variation in its activity [5]. Several polymorphisms of the CYP1A2 gene have been identified; some of them are significant and others are not.…”