VENLAFAXINE OXIDATION IN-VITRO IS CATALYZED BY CYP2D6

1 Several selective 5-HT reuptake inhibitors (SSRIs) are inhibitors of the genetically polymorphic drug metabolizing enzyme, CYP2D6. We stud ied the interaction of venlafaxine, a new SSRI, with CYP2D6 in human l iver microsomes. 2 Venlafaxine was a less potent inhibitor of this enz yme activity in vitro than other SSRIs tested. The average apparent K- i values determined using CYP2D6-dependent dextromethorphan O-demethyl ation were: 33, 52 and 22 mu M for rac-venlafaxine, R(+)-venlafaxine a nd S(-)-venlafaxine, respectively, vs 0.065 to 1.8 mu M for paroxetine , fluoxetine, norfluoxetine, fluvoxamine and sertraline. 3 Microsomes from human livers (n = 3) and from yeast transformed with an expressio n plasmid containing human CYP2D6 cDNA catalyzed the O-demethylation o f venlafaxine, which is the major metabolic pathway in vivo. Intrinsic metabolic clearance values (V-max/K-m) indicated that S(-)-venlafaxin e was cleared preferentially via this pathway. 4 In microsomes from CY P2D6-deficient livers (n = 2), V-max/K-m of O-demethylation of venlafa xine was one to two orders of magnitude lower and was similar to the r ate of N-demethylation. 5 Studies with chemical probes which preferent ially inhibit P450 isoforms suggested that CYP3A3/4 is involved in ven lafaxine N-demethylation. 6 These in vitro findings predict phenotypic differences in the kinetics of venlafaxine in vivo, although the clin ical importance of this is unclear as O-demethylvenlafaxine is pharmac ologically similar to the parent drug. The findings also predict relat ively limited pharmacokinetic interaction between venlafaxine and othe r CYP2D6 substrates.