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Clozapine pharmacokinetics and pharmacodynamics studied with CYP1A2-null miceSection of Clinical Pharmacology, Institute of Psychiatry 1 Windsor Walk, Denmark Hill, London SE5 8AF, UK; k.aitchison{at}iop.kcl.ac.uk
Mercer University Pharmacy Practice, Atlanta, GA, USA
Section of Genetic Epidemiology and Biostatistics, Institute of Psychiatry, Denmark Hill, London, UK
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
National Addiction Centre, Addiction Sciences Building, London, UK
Section of Clinical Pharmacology Institute of Psychiatry, Denmark Hill, London, UK
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 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.
Key Words: clozapine • CYP1A2 • cytochrome P450 • knockout • metabolism • pharmacodynamics • pharmacokinetics
Journal of Psychopharmacology, Vol. 14, No. 4,
353-359 (2000) This article has been cited by other articles:
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