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 μM for rac‐venlafaxine, R(+)‐venlafaxine and S(‐)‐venlafaxine, respectively,vs 0.065 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 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/Kmax 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.