RT Journal Article
SR Electronic
T1 Metabolism of Clozapine by cDNA-Expressed Human Cytochrome P450 Enzymes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1379
OP 1382
VO 25
IS 12
A1 Linnet, Kristian
A1 Olesen, Ole V.
YR 1997
UL http://dmd.aspetjournals.org/content/25/12/1379.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics