Metabolism of trimipramine in vitro by human CYP2D6 isozyme.
In vitro metabolism of the tricyclic antidepressant trimipramine using a commercial preparation of human CYP2D6 isozyme expressed in a human cell line is described. 2-Hydroxytrimipramine and a previously unreported metabolite, 2,10- or 2,11-dihydroxytrimipramine were isolated. Their structures were determined by gas chromatography/mass spectroscopy of underivatized and derivatized extracts. Acetylation of the new metabolite resulted in dehydration at C10 to give 10,11-dehydro-2-acetoxytrimipramine. No N-dealkylation of trimipramine was observed. Prior administration of quinidine produced a large reduction in the metabolic oxidation of trimipramine with CYP2D6 while prior administration of quinine had no effect. The use of this CYP2D6 isozyme preparation in vitro is of value in the identification of possible in vivo substrates for the human CYP2D6 isozyme.
Bolaji
O O
OO
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Coutts
R T
RT
Baker
G B
GB
D002460:Cell Line; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006900:Hydroxylation; D007527:Isoenzymes / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D013379:Substrate Specificity; D014299:Trimipramine / Q000031:analogs & derivatives / Q000302:isolation & purification / Q000378:metabolism*
D007527:Isoenzymes; C085056:10,11-dehydro-2-acetoxytrimipramine; C085054:2,10-dihydroxytrimipramine; C085053:2,11-dihydroxytrimipramine; C070661:2-hydroxytrimipramine; D014299:Trimipramine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6