Drug extrapyramidal side effects. CYP2D6 genotypes and phenotypes

Objective: Among Caucasians, a lack of cytochrome P ₄₅₀ enzyme CYP2D6 is observed in 5–10% of individuals, named poor metabolizers (PMs). A consequence may be an impaired metabolism of many drugs such as most of the psychotropic drugs with an increased risk of drug side effects. This enzyme is also involved in the metabolism of endogenous compounds, including neurotransmitters such as dopamine and dopamine-related neurotransmitters which play a role in the mechanism of action of extrapyramidal drug side effects. The present study investigates whether patients who have developed and those who have not developed extrapyramidal drug side effects differ in their CYP2D6 genotypes and phenotypes. Methods: The CP2D6 genotype (method involving restriction length fragment polymorphism and polymerase chain reaction-single strand conformation polymorphism) was determined in 65 drug-treated in-patients, and the CYP2D6 phenotype (with dextromethorphan probe) in 62 of them. Two groups were constituted, one with 22 patients who had developed extrapyramidal drug side effects, and the second with 43 patients without such side effects. Results: In the whole population, there was an over-representation of PM phenotypes – more marked in the first group than the second (45% vs 14%). Concerning the genotypes, we observed that the percentage of functional alleles (with extensive metabolic capacity) was higher in group 2, whereas the percentage of non-functional alleles (without metabolic activity) was higher in group 1; this frequency difference was only marginally significant (χ² 5.95; P < 0.0509; degrees of freedom=2). Consequently, there was a higher percentage of genotypes with no (extensive) functional alleles in the group of patients suffering from extrapyramidal side effects than in the other group (P < 0.00001). Conclusion: CYP2D6-impaired metabolic capacity may be a contributory factor in extrapyramidal drug side effects. Received: 25 May 1999 / Accepted in revised form: 18 August 1999