Venlafaxine serum levels and CYP2D6 genotype

Thirty-three patients with depression treated with 225 mg venlafaxine were genotyped for the polymorphic enzyme, debrisoquine 4-hydroxylase (CYP2D6). The relationship between drug and metabolite levels and between genotype an d clinical response were investigated. Although the number of responders in this study is insufficient for definite conclusions to be drawn, a target therapeutic concentration ranging from 195-400 mu g/L for the sum of venlaf axine and O-desmethylvenlafaxine is suggested. The ratio of O-desmethylvenl afaxine to venlafaxine in the serum concentrations is a measure of metaboli c turnover, and can be used to distinguish between ultrarapid and poor meta bolizers. All but one of the nonresponders in this study had lower ratios t han the responders. Three patients (9%) had homozygous defective CYP2D6 all eles and did not readily metabolize venlafaxine to O-desmethylvenlafaxine, pointing to poor metabolism. In these patients, N-desmethylation was increa sed. Two out of four patients detected by the ratio as potentially ultrarap id metabolizers were shown to have multiple copies of a functional CYP2D6 g ene.