Cytochrome P450 CYP2D6 is the most extensively characterized polymorphic drugmetabolizing enzyme. A de®ciency of the CYP2D6 enzyme is inherited as an autosomal recessive trait; these subjects (7% of Caucasians, about 1% of Orientals) are classi®ed as poor metabolizers. Among the rest (extensive metabolizers), enzyme activity is highly variable, from extremely high in ultrarapid metabolizers, to markedly reduced in intermediate metabolizers. The CYP2D6 gene is highly polymorphic, with more than 70 allelic variants described so far. Of these, more than 15 encode an inactive or no enzyme at all. Others encode enzyme with reduced,`normal' or increased enzyme activity. The CYP2D6 gene shows marked interethnic variability, with interpopulation differences in allele frequency and existence of`populationspeci®c' allelic variants, for instance among Orientals and Black Africans. The CYP2D6 enzyme catalyses the metabolism of a large number of clinically important drugs including antidepressants, neuroleptics, some antiarrhythmics, lipophilic b-adrenoceptor blockers and opioids. The present-day knowledge on the in¯uence of the genetic variability in CYP2D6 on the clinical pharmacokinetics and therapeutic effects/adverse effects of psychotropic drugs is reviewed.

The results of this study show the quantitative importance of the CYP2D6 genotype, especially the presence of multiple functional CYP2D6 genes for the pharmacokinetics of nortriptyline and 10-hydroxynortriptyline. Genotyping of subjects with multiple copies of functional genes may be of great value for differentiating ultrarapid metabolizers from patients who do not comply with the prescription and for assuring adequate drug choice and dosage for these patients.

The administration of drugs together suggests an inhibition of debrisoquin metabolism caused by the concurrent drugs given. By separating debrisoquin from the other cocktail drugs, this method is likely to be used as a tool to phenotype the enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 with only 2 urinary collections and 2 blood-sampling occasions.

Tolterodine is extensively metabolized by CYP2D6 with high specificity. Despite the effect on pharmacokinetics, the CYP2D6 polymorphism does not appear to be of great importance in the antimuscarinic effect, probably because of the additive action of parent drug and active metabolite.

The authors describe a 33-year-old woman who experienced severe pain in the epigastrium after codeine intake. This side-effect is consistent with that of morphine. Later, the patient was phenotyped and genotyped as an ultrarapid metabolizer with high capacity to metabolize codeine to morphine.

The CYP2D6*10 allele in Chinese subjects was associated with significantly higher plasma levels of nortriptyline compared with the CYP2D6*1 allele because of an impaired metabolism of nortriptyline to 10-hydroxynortriptyline, particularly in the subjects with the CYP2D6*10/*10 genotype. The results suggest that genotyping of CYP2D6 may be a useful tool in predicting the pharmacokinetics of nortriptyline.

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