Cytochrome P-450 enzymes and FMO3 contribute to the disposition of the antipsychotic drug perazine in vitro.
BACKGROUND
Perazine (PER) is a phenothiazine antipsychotic drug frequently used in Germany that undergoes extensive metabolism.


OBJECTIVE
To anticipate metabolic drug interactions and to explore the relevance of polymorphisms of metabolic enzymes, perazine-N-demethylation and perazine-N-oxidation were investigated in vitro using human liver microsomes and cDNA expressed enzymes.


RESULTS
CYP3A4 and CYP2C9 were identified as the major enzymes mediating PER-N-demethylation. At 10 microM PER, a concentration consistent with anticipated in vivo liver concentrations, CYP3A4 and CYP2C9 contributed 50% and 35%, respectively, to PER-N-demethylation. With increasing PER concentrations, contribution of CYP2C9 decreased and CYP3A4 became more important. In human liver microsomes, PER-N-demethylation was inhibited by ketoconazole (>40%) and sulfaphenazole (16%). Allelic variants of recombinant CYP2C9 showed differences in PER-N-demethylase activity. The wild type allele CYP2C9*1 was the most active variant. Maximal activities of CYP2C9*2 and CYP2C9*3 were 88% and 18%, respectively, compared to the wild type activity. Perazine-N-oxidation was mainly mediated by FMO3. In the absence of NADPH, heat treatment of microsomes abolished PER-N-oxidase activity. Methimazole inhibited PER-N-oxidation, while CYP specific inhibitors had no inhibitory effect. Perazine is a potent inhibitor of dextromethorphan-O-demethylase, S-mephenytoin-hydroxylase, alprazolam-4-hydroxylase, phenacetin-O-deethylase and tolbutamide-hydroxylase activity in human liver microsomes.


CONCLUSIONS
Alterations in the activity of CYP3A4, CYP2C9 and FMO3 through genetic polymorphisms, enzyme induction or inhibition bear the potential to cause clinically significant changes in perazine clearance. PER may alter the clearance of coadministered compounds metabolized by CYP2D6, CYP2C19, CYP2C9, CYP3A4 and CYP1A2.
Störmer
E
E
Humboldt-University Berlin, Institute of Clinical Pharmacology, Germany.
Brockmöller
J
J
Roots
I
I
Schmider
J
J
D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D019388:Cytochrome P-450 CYP1A2; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D003640:Dealkylation; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000502:physiology; D010105:Oxygenases / Q000502:physiology*; D010464:Perazine / Q000493:pharmacokinetics*; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000502:physiology
D014150:Antipsychotic Agents; D010464:Perazine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010105:Oxygenases; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C020066:dimethylaniline monooxygenase (N-oxide forming); D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D039181:Steroid 16-alpha-Hydroxylase; C510163:CYP3A4 protein, human