Venlafaxine oxidationin vitrois catalysed by CYP2D6

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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 activityin vitrothan other SSRIs tested. The average apparentKivalues determined using CYP2D6‐dependent dextromethorphanO‐demethylation were: 33, 52 and 22 μM for rac‐venlafaxine, R(+)‐venlafaxine and S(‐)‐venlafaxine, respectively,vs0.065 to 1.8 μM 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 theO‐demethylation of venlafaxine, which is the major metabolic pathwayin vivo.Intrinsic metabolic clearance values (Vmax/Km) indicated that S(‐)‐venlafaxine was cleared preferentiallyviathis pathway.4 In microsomes from CYP2D6‐deficient livers (n= 2),Vmax/KmaxofO‐demethylation of venlafaxine was one to two orders of magnitude lower and was similar to the rate ofN‐demethylation.5 Studies with chemical probes which preferentially inhibit P450 isoforms suggested that CYP3A3/4 is involved in venlafaxineN‐demethylation.6 Thesein vitrofindings predict phenotypic differences in the kinetics of venlafaxinein vivo, although the clinical importance of this is unclear asO‐demethylvenlafaxine is pharmacologically similar to the parent drug. The findings also predict relatively limited pharmacokinetic interaction between venlafaxine and other CYP2D6 substrates.

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