Journal
JOURNAL OF PSYCHOPHARMACOLOGY
Volume 14, Issue 4, Pages 353-359Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1177/026988110001400403
Keywords
clozapine; CYP1A2; cytochrome P450; knockout; metabolism; pharmacodynamics; pharmacokinetics
Funding
- NATIONAL CANCER INSTITUTE [ZIABC005562, Z01BC005562] Funding Source: NIH RePORTER
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available