CYP2D6 genotype and venlafaxine-XR concentrations in depressed elderly.
BACKGROUND
The elderly are at increased risk for medication-related adverse events. Recent reports indicate that venlafaxine may put the elderly at increased risk of cardio- and cerebrovascular adverse events. We investigated the relationship between the CYP2D6 polymorphism and steady-state plasma concentration of venlafaxine (VEN) and its primary metabolite o-desmethylvenlafaxine (ODV) in elderly participants receiving venlafaxine-XR for major depression in order to explore the contribution of pharmacogenetics to medication tolerability.


METHODS
Forty-six elderly participants received venlafaxine-XR for the treatment of major depression. CYP2D6 genotype and steady-state plasma levels of VEN and ODV were determined.


RESULTS
Sixty-five percent of participants were homozygous of the wild type (WT) allele, whereas 35% carried one or more variant alleles associated with intermediate and poor 2D6 metabolizer status. VEN concentration per unit dose was significantly higher and ODV concentration per unit dose was significantly lower in participants who carried one or more variant alleles compared to participants who were homozygous for the WT allele. The VEN and ODV concentrations per unit dose were also correlated with creatinine clearance. CYP2D6 genotype was not associated with medication associated side-effects.


CONCLUSIONS
Plasma dose-corrected concentrations of VEN and ODV correlated with genetically determined CYP2D6 enzymatic activity in depressed elders treated with venlafaxine-XR. This relationship was not masked by the effects of age-related illness or polypharmacy. Future clinical application of pharmacogenetics to examine 2D6-dependent medications may help reduce the incidence of medication adverse events particularly in those elders at higher risk for medication adverse events due to impaired renal or cardiac function.
Whyte
Ellen M
EM
Western Psychiatric Institute and Clinic, Department of Psychiatry, University of Pittsburgh School of Medicine, USA.
Romkes
Marjorie
M
Mulsant
Benoit H
BH
Kirshne
Margaret A
MA
Begley
Amy E
AE
Reynolds
Charles F
CF
Pollock
Bruce G
BG
D000368:Aged; D000369:Aged, 80 and over; D018687:Antidepressive Agents, Second-Generation / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use; D003404:Creatinine / Q000378:metabolism; D003511:Cyclohexanols / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003865:Major Depressive Disorder / Q000097:blood / Q000235:genetics*; D000069468:Desvenlafaxine Succinate; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D000069470:Venlafaxine Hydrochloride
D018687:Antidepressive Agents, Second-Generation; D003511:Cyclohexanols; D000069470:Venlafaxine Hydrochloride; D003404:Creatinine; D019389:Cytochrome P-450 CYP2D6; D000069468:Desvenlafaxine Succinate