Abstract
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.
Conclusion
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.
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Hermann, M., Hendset, M., Fosaas, K. et al. Serum concentrations of venlafaxine and its metabolites O-desmethylvenlafaxine and N-desmethylvenlafaxine in heterozygous carriers of the CYP2D6*3, *4 or *5 allele. Eur J Clin Pharmacol 64, 483–487 (2008). https://doi.org/10.1007/s00228-007-0453-7
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DOI: https://doi.org/10.1007/s00228-007-0453-7