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 under 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 later for determination of dextromethorphan and metabolites in serum. For comparison, urine was collected over 8 h after ingestion of 20 mg dextromethorphan in a separate test. The CYP2D6 phenotype was determined from the ratio of dextromethorphan to dextrorphan. For genotyping, mutant 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 dextromethorphan to dextrorphan ranged from 0.01-2.53 in serum and from 0.0007-4.252 in urine. Probit analysis of serum ratios revealed a bimodal distribution with an antimode at 0.126. According to this antimode, control subjects exhibited identical phenotypes and genotypes, whereas patients under paroxetine, moclobemide or metoprolol who had been genotyped as extensive metabolizers were poor metabolizer phenotypes. Administration of tricyclic antidepressants did not change the CYP2D6 phenotype. The serum assay was more rapid and more accurate than the standard urine approach. Therefore the determination of dextromethorphan and metabolites in serum could be advantageous to measure individual CYP2D6 activities in vivo and thus optimize the dosing of drugs metabolized by CYP2D6.
Köhler
D
D
Department of Psychiatry, University of Mainz, Germany.
Härtter
S
S
Fuchs
K
K
Sieghart
W
W
Hiemke
C
C
D000328:Adult; D019389:Cytochrome P-450 CYP2D6 / Q000097:blood* / Q000235:genetics* / Q000652:urine; D003915:Dextromethorphan / Q000097:blood* / Q000493:pharmacokinetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011619:Psychotropic Drugs / Q000627:therapeutic use*
D011619:Psychotropic Drugs; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6