Venlafaxine oxidation in vitro is catalysed by CYP2D6

Br J Clin Pharmacol. 1996 Feb;41(2):149-56. doi: 10.1111/j.1365-2125.1996.tb00173.x.

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 microM for rac-venlafaxine, R(+)-venlafaxine and S(-)-venlafaxine, respectively, vs 0.065 to 1.8 microM 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/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 O-demethylvenlafaxine is pharmacologically similar to the parent drug. The findings also predict relatively limited pharmacokinetic interaction between venlafaxine and other CYP2D6 substrates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalysis
  • Cyclohexanols / metabolism*
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 CYP2D6 / metabolism*
  • Humans
  • Methylation
  • Microsomes, Liver / enzymology*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Serotonin Uptake Inhibitors / metabolism*
  • Venlafaxine Hydrochloride

Substances

  • Cyclohexanols
  • Recombinant Proteins
  • Serotonin Uptake Inhibitors
  • Venlafaxine Hydrochloride
  • Cytochrome P-450 CYP2D6