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 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.

O- and N-demethylation of Venlafaxine In Vitro by Human Liver Microsomes and by Microsomes from cDNA-Transfected Cells Effect of Metabolic Inhibitors and SSRI Antidepressants

“…Our data obtained through the use of multiple experimental methods agrees with, but extends previous studies using only human liver microsomes (Otton et al 1996). Several recent studies have used a combination of methods to achieve a better understanding of the NEUROPSYCHOPHARMACOLOGY 1999-VOL.…”

“…ODV has a receptor affinity profile similar to its parent compound VF, while the latter two metabolites have little if any affinity for the above receptor sites (Muth et al 1991). Previous studies have shown that the biotransformation of VF to ODV is mediated by CYP2D6, and NDV via CYP3A3 ր 4, and possibly a second enzyme (Otton et al 1996).…”

“…Previous studies have examined the inhibitory potency of SSRIs on CYP2D6 mediated reactions (Table 5). In general, PX, FLU, and NOR are strong inhibitors of CYP2D6 mediated reactions, while SER, DES, and FX are weaker.The kinetics of NDV formation in human liver microsomes were determined using concentrations up to 20,000 M, which is higher than the maximum (500 M) used in previous studies (Otton et al 1996). Although a single unique enzyme kinetic mechanism for NDV formation could not be clearly identified, a one enzyme model (equation 3) adequately fit the data and allowed us to compare kinetic parameters in a relative fashion (Table 2).…”

“…ODV has a receptor affinity profile similar to its parent compound VF, while the latter two metabolites have little if any affinity for the above receptor sites (Muth et al 1991). Previous studies have shown that the biotransformation of VF to ODV is mediated by CYP2D6, and NDV via CYP3A3 ր 4, and possibly a second enzyme (Otton et al 1996).We used an in vitro model of human liver microsomal preparations and of microsomes containing individual human cytochromes expressed by cDNA-transfected human lymphoblastoid cells, to evaluate the biotransformation of VF to its principal metabolites ODV and NDV over a large range of substrate concentrations. We also assessed the inhibitory potencies of the currently available SSRIs and their metabolites.…”

Venlafaxine induced hepatotoxicity in a carcinoma of breast survivor with co-morbid depression

“…It is metabolized by CYP 2D6 isoenzyme of cytochrome P450. 4 VEN induced hepatotoxicity is rare but a life threatening adverse effect and reported in 0.4% of patients. 5 The mechanism for liver injury due to VEN is either immunoallergic in nature, metabolic or due to its intermediate…”