The N-demethylation of the doxepin isomers is mainly catalyzed by the polymorphic CYP2C19.
OBJECTIVE
This study was conducted to identify the cytochrome P450s (CYPs) responsible for the metabolism of the cis- and trans-isomers of the tricyclic antidepressant doxepin to its pharmacologically active N-desmethylmetabolite by in vitro techniques.


METHODS
The doxepin N-demethylation was studied by means of pooled human liver microsomes and chemical inhibitors, recombinant human (rh)-CYPs, and geno- and phenotyped human liver microsomes.


RESULTS
The N-demethylation of both isomers was inhibited most prominently by tranylcypromine (CYP2C19) to more than 50%. Furafylline (CYP1A2) and sulfaphenazole (CYP2C9) inhibited the N-demethylation to a lesser extent while quinidine (CYP2D6) or troleandomycine (CYP3A4) had no effect. Rh-CYP2C19, -CYP1A2, and -CYP2C9 were able to N-demethylate cis- and trans-doxepin. Only traces of trans-desmethyldoxepin were detectable when CYP3A4 was used. The maximum velocity in the cis- and transdoxepin N-demethylation was significantly (P < 0.05) lower in microsomes with low CYP2C19 activity (345 +/- 44 and 508 +/- 75 pmol/min/ mg protein, respectively) compared to those with high CYP2C19 activity (779 +/- 132 and 1,189 +/- 134 pmollmin/mg).


CONCLUSIONS
The present study demonstrates a significant contribution of the polymorphic CYP2C19 to the N-demethylation of doxepin. CYP2C9 and CYP1A2 play a minor role and CYP3A4 does not contribute substantially.
Department of Psychiatry, University of Mainz, Germany. sepp@psychiatrie.klinik.uni-mainz.de
Sebastian
S
Härtter
Gunnel
G
Tybring
Thomas
T
Friedberg
Harald
H
Weigmann
Christoph
C
Hiemke
D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002384:Catalysis; D065731:Cytochrome P-450 CYP2C19; D004316:Doxepin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D017879:Isothiocyanates / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014191:Tranylcypromine / Q000494:pharmacology
D007527:Isoenzymes; D017879:Isothiocyanates; D004316:Doxepin; D014191:Tranylcypromine; C058305:phenethyl isothiocyanate; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; C028701:desmethyldoxepin