title: Effect of cytochrome P450 enzyme polymorphisms on pharmacokinetics of venlafaxine.
abstract: This study examines the relationship between blood concentrations of venlafaxine and its active metabolite, O-desmethyl venlafaxine (ODV), and genetic variants of the cytochrome P450 enzymes CYP2D6 and CYP2C19 in human subjects. Trough blood concentrations were measured at steady state in patients treated with venlafaxine extended release in a clinical practice setting. CYP2D6 and CYP2C19 genotypes were converted to activity scores based on known activity levels of the two alleles comprising a genotype. After adjusting for drug dose and gender effects, higher CYP2D6 and CYP2C19 activity scores were significantly associated with lower venlafaxine concentrations (P < 0.001 for each). Only CYP2D6 was associated with the concentration of ODV (P < 0.001), in which genotypes with more active alleles were associated with higher ODV concentrations. The sum of venlafaxine plus ODV concentration showed the same pattern as venlafaxine concentrations with CYP2D6 and CYP2C19 genotypes with higher activity scores being associated with a lower venlafaxine plus ODV concentration (2D6 P = 0.01; 2C19 P < 0.001). Because allelic variants in both CYP2D6 and CYP2C19 influence the total concentration of the active compounds venlafaxine and ODV, both CYP2D6 and CYP2C19 genotypes should be considered when using pharmacogenomic information for venlafaxine dose alterations.
authors.affiliation: Mayo Clinic College of Medicine, Rochester, MN 55905, USA. mcalpine.donald@mayo.edu
authors.forename: Donald E
authors.initials: DE
authors.lastname: McAlpine
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Biernacka
authors.forename: David A
authors.initials: DA
authors.lastname: Mrazek
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: O'Kane
authors.forename: Susanna R
authors.initials: SR
authors.lastname: Stevens
authors.forename: Loralie J
authors.initials: LJ
authors.lastname: Langman
authors.forename: Vicki L
authors.initials: VL
authors.lastname: Courson
authors.forename: Jyoti
authors.initials: J
authors.lastname: Bhagia
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Moyer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D003511:Cyclohexanols / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000069470:Venlafaxine Hydrochloride; D055815:Young Adult
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D003511:Cyclohexanols; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride; C045793:CYP2C19 protein, human