Prediction of phenotype for dextromethorphan O-demethylation by using polymerase chain reaction in healthy volunteers.
The polymorphism of dextromethorphan (CAS 125-71-3) metabolism is dependent on hepatic cytochrom P4502D6 (CYP2D6) activity. The relationship between the CYP2D6 genotype and the dextromethorphan phenotype was studied in 83 healthy unrelated subjects. Genotype was determined by allele-specific polymerase chain reaction (PCR). Phenotyping was performed by administration of 25 mg dextromethorphan hydrobromide and determination of the urinary metabolic ratio of dextromethorphan and its O-demethylated metabolite dextrorphan (DEM/DOR). Six subjects (7.2%) were homozygous for mutant alleles (95% confidence interval 2.7%-14.7%), 18 subjects (22%) were heterozygous carriers, and 59 were homozygous for the wild-type allele. Six subjects were classified as poor metabolizers (PM) of dextromethorphan, 77 as extensive metabolizers (EM). Genotyping correctly predicted all PMs and EMs. The CYP2D6-B mutation was most frequently found, being present in 83% of PM and 8% of EM alleles. Heterozygous EMs (22% of the total population studied) were significantly underrepresented compared to the expected genotype frequency of 31% (p < 0.05). The extensive metabolizers who were heterozygous for the wild-type allele had a significantly higher metabolic ratio, compared to the homozygous EMs (log10DEM/DOR [95% = -1.99 [(-2.30)-(-1.69)] vs. -2.55 [(-2.67)-(-2.43)]; p < 0.001), indicating a gene-dose effect for CYP2D6.
Zimmermann
T
T
Forschung und Entwicklung, Pfizer/Mack, Illertissen, Fed. Rep. of Germany.
Schlenk
R
R
Pfaff
G
G
Lach
P
P
Wildfeuer
A
A
D000328:Adult; D000483:Alleles; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004247:DNA / Q000032:analysis; D003640:Dealkylation; D003915:Dextromethorphan / Q000378:metabolism* / Q000652:urine; D003917:Dextrorphan / Q000652:urine; D005260:Female; D005838:Genotype; D006801:Humans; D007962:Leukocytes / Q000201:enzymology / Q000378:metabolism; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic
D003917:Dextrorphan; D003915:Dextromethorphan; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6