Venlafaxine oxidation in vitro is catalysed by CYP2D6

摘要

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 K i 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 ( V max / K m ) indicated that S(-)-venlafaxine was cleared preferentially via this pathway. 4 In microsomes from CYP2D6-deficient livers ( n = 2), V max / K max 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.