Metabolic activity of dextromethorphan O-demethylation in healthy Japanese volunteers carrying duplicated CYP2D6 genes: duplicated allele of CYP2D6*10 does not increase CYP2D6 metabolic activity.
BACKGROUND
This study was designed to assess the metabolic activities of dextromethorphan O-demethylation in healthy Japanese subjects carrying duplicated CYP2D6 alleles, CYP2D6*1 x 2, CYP2D6*2 x 2 or CYP2D6*10 x 2.


METHODS
Forty-one unrelated healthy Japanese subjects containing carriers who had previously been genotyped as CYP2D6*1 x 2/*2, CYP2D6*1/*2 x 2, and CYP2D6*10/*10 x 2 were phenotyped with dextromethorphan.


RESULTS
The metabolic ratios of dextromethorphan/dextrorphan in subjects with CYP2D6*1 x 2/*2 or CYP2D6*1/*2 x 2 were lower than those in subjects with CYP2D6*1/*2, while the metabolic ratios in subjects with CYP2D6*10/*10 x 2, as well as homozygotes for CYP2D6*10, were significantly (P<0.01) higher than those in homozygotes for CYP2D6*1.


CONCLUSIONS
The results suggested that carriers with three functional CYP2D6 genes, CYP2D6*1 x 2/*2 or CYP2D6*1/*2 x 2, are ultrarapid metabolizer phenotypes in Japanese. The results also suggested that there is no gene-dose effect with the dextromethorphan O-demethylation activities between carriers with two and three CYP2D6*10 mutated genes per genome. Therefore, CYP2D6*10 x 2 may play an important role for the treatment of Japanese patients as well as CYP2D6*10 which is mainly responsible for the intermediate metabolizers in Japanese.
Ishiguro
Akihiro
A
Department of Pharmacy, Faculty of Medicine, University of Tokyo Hospital, 7-3-1 Hongoh, Bunkyo, Tokyo 113-8655, Japan.
Kubota
Takahiro
T
Ishikawa
Hiroshi
H
Iga
Tatsuji
T
D000328:Adult; D001711:Biotransformation; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003915:Dextromethorphan / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D003917:Dextrorphan / Q000032:analysis; D005260:Female; D018628:Gene Dosage; D020440:Gene Duplication; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D008745:Methylation; D008875:Middle Aged; D010597:Pharmacogenetics
D003917:Dextrorphan; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6