title: Venlafaxine oxidation in vitro is catalysed by CYP2D6.
abstract: 1. Several selective 5-HT reuptake inhibitors (SSRIs) are inhibitors of the genetically polymorphic drug metabolizing enzyme, CYP2D6. We studied the interaction of venlafaxine, a new SSRI, with CYP2D6 in human liver microsomes. 2. Venlafaxine was a less potent inhibitor of this enzyme activity in vitro than other SSRIs tested. The average apparent Ki values determined using CYP2D6-dependent dextromethorphan O-demethylation were: 33, 52 and 22 microM for rac-venlafaxine, R(+)-venlafaxine and S(-)-venlafaxine, respectively, vs 0.065 to 1.8 microM for paroxetine, fluoxetine, norfluoxetine, fluvoxamine and sertraline. 3. Microsomes from human livers (n = 3) and from yeast transformed with an expression plasmid containing human CYP2D6 cDNA catalyzed the O-demethylation of venlafaxine, which is the major metabolic pathway in vivo. Intrinsic metabolic clearance values (Vmax/Km) indicated that S(-)-venlafaxine was cleared preferentially via this pathway. 4. In microsomes from CYP2D6-deficient livers (n = 2), Vmax/Km of O-demethylation of venlafaxine was one to two orders of magnitude lower and was similar to the rate of N-demethylation. 5. Studies with chemical probes which preferentially inhibit P450 isoforms suggested that CYP3A3/4 is involved in venlafaxine N-demethylation. 6. These in vitro findings predict phenotypic differences in the kinetics of venlafaxine in vivo, although the clinical importance of this is unclear as O-demethylvenlafaxine is pharmacologically similar to the parent drug. The findings also predict relatively limited pharmacokinetic interaction between venlafaxine and other CYP2D6 substrates.
authors.affiliation: Clinical Research and Treatment Institute, Addiction Research Foundation, Toronto, Ontario, Canada.
authors.forename: S V
authors.initials: SV
authors.lastname: Otton
authors.forename: S E
authors.initials: SE
authors.lastname: Ball
authors.forename: S W
authors.initials: SW
authors.lastname: Cheung
authors.forename: T
authors.initials: T
authors.lastname: Inaba
authors.forename: R L
authors.initials: RL
authors.lastname: Rudolph
authors.forename: E M
authors.initials: EM
authors.lastname: Sellers
mesh_terms: D002384:Catalysis; D003511:Cyclohexanols / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D008862:Microsomes, Liver / Q000201:enzymology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism*; D000069470:Venlafaxine Hydrochloride
chemical_list: D003511:Cyclohexanols; D019389:Cytochrome P-450 CYP2D6; D011994:Recombinant Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride