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 CY P2D6-dependent dextromethorphan 0-demethylation were: 33, 52 and 22 PM for rac-venlafaxine, R( +)-venlafaxine and S (-)-venlafaxine, respectively, us 0.065 to 1.8 p~ 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 0-demethylation of venlafaxine, which is the major metabolic pathway in uiuo. 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 0-demethylvenlafaxine is pharmacologically similar to the parent drug. The findings also predict relatively limited pharmacokinetic interaction between venlafaxine and other CYP2D6 substrates.
Background: Indirect evidence suggests that the antidepressant venlafaxine hydrochloride selectively inhibits serotonin (5-HT) uptake at low doses, whereas at high doses, it inhibits both 5-HT and norepinephrine (NE) uptake. We hypothesized that, in vivo, both high and low doses would inhibit the 5-HT uptake of platelets but that the higher dose would differentially blunt the pressor response to tyramine, a marker for NE uptake.
This study is the first placebo-controlled demonstration of the long-term efficacy of any drug class in treating outpatients with DSM-IV-diagnosed GAD. Venlafaxine XR is an effective, rapidly acting, safe, once-daily agent for both the short- and long-term treatment of anxiety and may provide an important alternative to currently available anxiolytics. JAMA. 2000.
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