Venlafaxine metabolism as a marker of cytochrome P450 enzyme 2D6 metabolizer status.
BACKGROUND
One of the major enzymes of the cytochrome P450 drug-metabolizing system, CYP2D6, shows a high degree of genetic polymorphism and variability in activity. Based on the degree of CYP2D6 activity, individuals can be broadly classified as poor metabolizers (PMs) or extensive metabolizers (EMs); the metabolism of CYP2D6 substrates differs among PMs and EMs. The metabolism of various drugs that are substrates of CYP2D6 has been used as a marker for metabolic phenotype, calculating the plasma or urinary metabolic ratio of the parent compound to its metabolite. The current analysis evaluates the use of the O-desmethylvenlafaxine-venlafaxine ratio (ODV/VEN) after administration of VEN, a CYP2D6 substrate, for determining CYP2D6 metabolic phenotype in healthy adults receiving VEN.


METHODS
The analysis included data from 2 studies in which healthy adults were classified as either EMs or PMs using established methods (1 genotypic and 1 phenotypic) and were then administered VEN at daily dosages ranging from 75 to 150 mg. Blood plasma samples were taken at various time points, and the ODV/VEN ratio was calculated.


RESULTS
Blood samples from 28 participants in the 2 studies were available for analysis. The ODV/VEN ratio distinguished the EM and PM phenotypes; ratios were 1 or greater for EMs and less than 1 for PMs at 4 hours after dose administration.


CONCLUSIONS
The ratio of ODV/VEN is an effective means of phenotyping individuals according to their CYP2D6 metabolizer status.
Nichols
Alice I
AI
Wyeth Research, 500 Arcola Rd, Collegeville, PA 19426, USA. nichola2@wyeth.com
Lobello
Kasia
K
Guico-Pabia
Christine J
CJ
Paul
Jeff
J
Preskorn
Sheldon H
SH
D000284:Administration, Oral; D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000328:Adult; D001711:Biotransformation; D002986:Clinical Trials as Topic; D003511:Cyclohexanols / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D000069468:Desvenlafaxine Succinate; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011237:Predictive Value of Tests; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013379:Substrate Specificity; D000069470:Venlafaxine Hydrochloride; D055815:Young Adult
D018759:Adrenergic Uptake Inhibitors; D003511:Cyclohexanols; D019389:Cytochrome P-450 CYP2D6; D000069468:Desvenlafaxine Succinate; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride