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

Abstract Background: This study was designed to assess the metabolic activities of dextromethorphan O -demethylation in healthy Japanese subjects carrying duplicated CYP2D6 alleles, CYP2D6*1×2 , CYP2D6*2×2 or CYP2D6*10×2 . Methods: Forty-one unrelated healthy Japanese subjects containing carriers who had previously been genotyped as CYP2D6*1×2/*2 , CYP2D6*1/*2×2 , and CYP2D6*10/*10×2 were phenotyped with dextromethorphan. Results: The metabolic ratios of dextromethorphan/dextrorphan in subjects with CYP2D6*1×2/*2 or CYP2D6*1/*2×2 were lower than those in subjects with CYP2D6*1/*2 , while the metabolic ratios in subjects with CYP2D6*10/*10×2 , as well as homozygotes for CYP2D6*10 , were significantly ( P CYP2D6*1 . Conclusions: The results suggested that carriers with three functional CYP2D6 genes, CYP2D6*1×2/*2 or CYP2D6*1/*2×2 , 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*10×2 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.