CYP2D6 GENOTYPE AND PHENOTYPING BY DETERMINATION OF DEXTROMETHORPHAN AND METABOLITES IN SERUM OF HEALTHY CONTROLS AND OF PATIENTS UNDER PSYCHOTROPIC MEDICATION

Fourteen drug free healthy volunteers and 22 psychiatric patients unde r psychotropic medication were phenotyped for their individual CYP2D6 activity using dextromethorphan as a probe drug. A solution containing 20 mg dextromethorphan was administered and blood was taken 60 min la ter for determination of dextromethorphan and metabolites in serum. Fo r comparison, urine was collected over 8 h after ingestion of 20 mg de xtromethorphan in a separate test. The CYP2D6 phenotype was determined from the ratio of dextromethorphan to dextrorphan. For genotyping, mu tant alleles of the CYP2D6 gene were identified using allele-specific polymerase chain reactions. Genotyping revealed five poor metabolizers of CYP2D6. The others were extensive metabolizers. The ratio of dextr omethorphan to dextrorphan ranged from 0.01-2.53 in serum and from 0.0 007-4.252 in urine. Probit analysis of serum ratios revealed a bimodal distribution with an antimode at 0.126. According to this antimode, c ontrol subjects exhibited identical phenotypes and genotypes, whereas patients under paroxetine, moclobemide or metoprolol who had been geno typed as extensive metabolizers were poor metabolizer phenotypes. Admi nistration of tricyclic antidepressants did not change the CYP2D6 phen otype. The serum assay was more rapid and more accurate than the stand ard urine approach. Therefore the determination of dextromethorphan an d metabolites in serum could be advantageous to measure individual CYP 2D6 activities in vivo and thus optimize the dosing of drugs metaboliz ed by CYP2D6.