The N-demethylation of the doxepin isomers is mainly catalyzed by the polymorphic CYP2C19.

Article Details

Citation

Hartter S, Tybring G, Friedberg T, Weigmann H, Hiemke C

The N-demethylation of the doxepin isomers is mainly catalyzed by the polymorphic CYP2C19.

Pharm Res. 2002 Jul;19(7):1034-7.

PubMed ID
12180536 [ View in PubMed
]
Abstract

PURPOSE: 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). CONCLUSION: 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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
DoxepinCytochrome P450 1A2ProteinHumans
No
Substrate
Details
DoxepinCytochrome P450 2C19ProteinHumans
No
Substrate
Details
DoxepinCytochrome P450 2C9ProteinHumans
No
Substrate
Details
DoxepinCytochrome P450 3A4ProteinHumans
No
Substrate
Details