Abstract
The metabolism of clozapine was studied in vitro using cDNA-expressed human cytochrome P450 (CYP) enzymes 1A2, 3A4, 2C9, 2C19, 2D6, and 2E1. CYP1A2, 3A4, 2C9, 2C19, and 2D6 were able toN-demethylate clozapine. N-Oxide formation was exclusively catalyzed by CYP3A4. CYP2E1 did not metabolize clozapine. With regard to quantitative relationships, CYP1A2, 2C9, 2C19, and 2D6 displayed KM values ranging from 13 to 25 μM, whereas CYP3A4 had a 5–10 times higherKM value. CYP2C19 and 2D6 had the highestVmax values (149–366 mol/hr/mol CYP). Taking into account the typical relative distribution of amounts of CYP enzymes in the liver, a simulation study suggested that at therapeutic concentrations CYP2C19 and CYP3A4 each accounted for about 35% of the metabolism. At toxic concentrations, the relative importance of CYP3A4 increased.
Footnotes
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Send reprint requests to: Dr. Kristian Linnet, Institute for Basic Psychiatric Research, Department of Biological Psychiatry, Psychiatric Hospital in Aarhus, Aarhus University Hospital, DK-8240 Risskov, Denmark.
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This work was supported by The Psychiatric Research Foundation, The Novo Nordisk Research Foundation, The Lundbeck Foundation, and Geert Jorgensen’s Foundation.
- Abbreviation used is::
- CYP
- cytochrome P450
- Received May 16, 1997.
- Accepted August 11, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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