Serum concentrations of venlafaxine and its metabolites O-desmethylvenlafaxine and N-desmethylvenlafaxine in heterozygous carriers of the CYP2D6*3, *4 or *5 allele.
OBJECTIVE
Increased systemic exposure of the antidepressant venlafaxine and increased risk of side effects has previously been observed in patients with defective CYP2D6 function [poor metabolisers (PMs)]. The aim of this study was to evaluate venlafaxine pharmacokinetics in carriers of one functional and one defective CYP2D6 allele [heterozygous extensive metabolisers (HEMs)].


METHODS
Data was collected retrospectively from a therapeutic drug-monitoring database. All CYP-genotyped patients with steady-state serum concentration measurements of venlafaxine and metabolites were included in the study. Patients were divided in groups: *1/*1 [homozygous extensive metabolisers (EMs)], *1/*3, *4 or *5 (HEMs) and *4/*4 (PMs). Dose-adjusted serum concentrations of venlafaxine, O-desmethylvenlafaxine, N-desmethylvenlafaxine, and the metabolic ratio (O-desmethylvenlafaxine/venlafaxine) were compared between the different genotype groups.


RESULTS
The sum of venlafaxine and O-desmethylvenlafaxine serum concentrations was not significantly different between genotype groups. Metabolic ratio was 50% lower in HEMs (n = 18) than in EMs (n = 20) (p < 0.05). Serum concentration of N-desmethylvenlafaxine was 5.5-fold higher in HEMs (p < 0.01) and 22-fold higher in PMs (p < 0.001) than in EMs.


CONCLUSIONS
The study showed a shift in the metabolic pathway resulting in substantially higher levels of N-desmethylvenlafaxine in HEMs than in EMs. The metabolic pattern of venlafaxine in HEMs was similar to previous observations in PMs and possibly represents an increased risk of venlafaxine-related side effects in HEM patients.
Hermann
M
M
Department of Psychopharmacology, Diakonhjemmet Hospital, P.O. Box 85, Vinderen N-0319, Oslo, Norway. monica.hermann@diakonsyk.no
Hendset
M
M
Fosaas
K
K
Hjerpset
M
M
Refsum
H
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D018687:Antidepressive Agents, Second-Generation / Q000097:blood*; D003511:Cyclohexanols / Q000097:blood*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D000069468:Desvenlafaxine Succinate; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000069470:Venlafaxine Hydrochloride
D018687:Antidepressive Agents, Second-Generation; D003511:Cyclohexanols; C434332:N-desmethylvenlafaxine; D000069470:Venlafaxine Hydrochloride; D019389:Cytochrome P-450 CYP2D6; D000069468:Desvenlafaxine Succinate