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Polymorphisms in the CYP 2D6 Gene: Association with Plasma Concentrations of Fluoxetine and Paroxetine

Charlier, Corinne PhD; Broly, Franck PhD; Lhermitte, Michel; Pinto, Emmanuel; Ansseau, Marc; Plomteux, Guy

Short Communication

Most antidepressants are metabolized by cytochrome P450 (CYP) 2D6, and it is well known that there may be significant interindividual variation in the capacity to metabolize xenobiotics. About 7 to 10% of whites are poor metabolisers (PM), and, on the contrary, about 5% are ultrarapid metabolizers (UM), inducing very different rates in the transformation of antidepressants extensively metabolized by CYP 2D6. CYP 2D6 polymorphism can be a potential risk factor for the development of side effects or a reason for the poor efficacy of the treatment. Various probe drugs may be used for phenotyping CYP 2D6, but genotyping is now available using leukocyte DNA and is independent of concomitant drug use. In this study, we used PCR-based methods for the identification of CYP 2D6 genotypes in 49 patients receiving standard doses of fluoxetine or paroxetine and found that plasma concentration of the antidepressant drugs was significantly correlated with genetic status. In one patient who displayed CYP 2D6 gene duplication (UM), paroxetine plasma concentration was extremely low. In PM fluoxetine-treated patients, drug plasma concentration was significantly higher than that seen in extensive metabolizers.

The cytochrome P450 (CYP) enzyme debrisoquine 4-hydroxylase, known as CYP 2D6, is involved in the oxidative metabolism of many different classes of commonly used drugs, including antidepressants. 1 The enzyme is highly genetically polymorphic, which results in metabolic capacity ranges between individuals from extremely slow to ultrafast. 1,2 About 7 to 10% of whites are poor metabolizers (PM), and such patients might develop adverse drug reactions when treated with standard doses of drug. 3 The majority of defective allelic variants of the CYP 2D6 gene that can give rise to the PM phenotype have now been identified. 1,2 By screening for all these null alleles, CYP 2D6 deficiency may be detectable with close to 100% accuracy. 4 In contrast, ultrarapid metabolizers (UM), with multiple CYP 2D6 genes, might require high doses of drugs for optimal therapy. 3 For ultrarapid metabolizers, treatment with standard recommended doses may produce lower steady-state plasma drug concentrations compared with the general population, leading to a nonresponder classification for the tested drug or to a noncompliance diagnosis if drug monitoring is performed. Both nonresponder classification and noncompliance accusation could be detrimental to a patient's course of therapy.

Because relatively simple PCR-based methods are now available for genotyping CYP 2D6, recent studies were conducted to elucidate the well-known variability of response to antidepressant therapy. 5,6 In the present study, 49 patients treated with fluoxetine or paroxetine—both drugs extensively metabolized by CYP 2D6—were genotyped, and plasma drug concentrations were determined at steady state.

From the Clinical Toxicology Laboratory (Dr Charlier and Mr Plomteux) and Psychiatric Unit (Mr Pinto and Mr Ansseau), University Hospital, CHU Sart Tilman, B-4000 Liège, Belgium, and †Toxicology Laboratory (Dr Broly and Mr Lhermitte, Hôpital Calmette, CHRU Lille, 59045 Lille Cedex, France

Received for publication January 1, 2003; accepted May 14, 2003.

Reprints: C. Charlier, Laboratoire de Toxicologie clinique Tour II, CHU Sart Tilman, 4000 Liège, Belgium. E-mail

© 2003 Lippincott Williams & Wilkins, Inc.