dextromethorphan and Basal-Ganglia-Diseases

Among Caucasians, a lack of cytochrome P450 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.. 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.. 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 nonfunctional alleles (without metabolic activity) was higher in group 1; this frequency difference was only marginally significant (chi 2 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).. CYP2D6-impaired metabolic capacity may be a contributory factor in extrapyramidal drug side effects.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Basal Ganglia Diseases; Cytochrome P-450 CYP2D6; Dextromethorphan; Excitatory Amino Acid Antagonists; Female; Genotype; Humans; Male; Middle Aged; Phenotype; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Prospective Studies; White People

This study examined the relationship between the metabolic ratios of dextromethorphan/dextrorphan, haloperidol disposition, and the incidence of extrapyramidal side effects in schizophrenic patients. Eighteen schizophrenic patients were phenotyped with a test dose of dextromethorphan prior to the initiation of haloperidol treatment. The metabolic ratio of dextromethorphan/dextrorphan was determined in each patient. Patients were treated with oral haloperidol 10 mg/day for 2 weeks. Blood samples for haloperidol and reduced haloperidol were obtained at week 2 of haloperidol treatment. Haloperidol and reduced haloperidol plasma concentrations were assayed by HPLC with electrochemical detection. Significant correlations of dextromethorphan/dextrorphan metabolic ratios vs. plasma haloperidol concentrations, reduced haloperidol concentrations, and reduced haloperidol/haloperidol ratios were found (r = 0.726, P = 0.0007; r = 0.782, P = 0.0001; and r = 0.619, P = 0.006, respectively). Ten patients who experienced extrapyramidal side effects had higher reduced haloperidol concentrations and reduced haloperidol/haloperidol ratios than the other patients (2.49 +/- 1.42 [S.D.] ng/ml vs. 1.10 +/- 0.46 ng/ml, P = 0.014 and 0.287 +/- 0.102 vs. 0.192 +/- 0.065, P = 0.030). The former also had a trend to have higher haloperidol concentrations and dextromethorphan/dextrorphan ratios than the latter (8.04 +/- 2.91 ng/ml vs. 5.83 +/- 1.79 ng/ml, P = 0.066 and 0.023 +/- 0.017 vs. 0.011 +/- 0.010, P = 0.077). Phenotyping patients has the potential to assist clinicians in predicting plasma drug concentrations during the subsequent neuroleptic drug treatment. Further research with phenotyping and psychotropic drug metabolism in psychiatric patients is needed.

Topics: Adult; Asian People; Basal Ganglia Diseases; Dextromethorphan; Female; Haloperidol; Humans; Male; Phenotype; Schizophrenia; White People