Haloperidol plasma concentration in Japanese psychiatric subjects with gene duplication of CYP2D6

Aims The cytochrome P-450 2D6 (CYP2D6) gene duplication/multiduplication producing an increase in enzyme activity, and the common Japanese mutation, CYP2D6star10A producing a decrease of enzyme activity were screened in a large number of Japanese psychiatric subjects (n = 111) in order to investigate whether these mutated alleles affected the plasma concentration of haloperidol. Methods Polymerase chain reaction-restriction fragment length polymorphism (PCR-PFLP) method was performed to identify the CYP2D6star10A and CYP2D6star2 genotypes in subjects who had been taking haloperidol. For the screening of duplicated active CYP2D6 gene, allele-specific long PCR was performed. Plasma concentration of haloperidol was measured by the enzyme immunoassay, and expressed as 'plasma concentration dose ratio' to normalize individual differences. Results The plasma concentration-dose ratio showed large interindividual differences of approximately 18-fold. PCR-PFLP methods revealed that 29 (26.1%), 10 (9.0%), 39 (35.1%), 0 (0%), seven (6.3%) and 26 (23.4%) cases possessed the CYP2D6 genotypes star1/star1, star1/star2, star1/star10A, star2/star2, star2/star10A and star10A/star10A, respectively. Six cases (5.4%) had duplicated CYP2D6 genes. There were no significant differences of plasma concentration-dose ratio between the groups classified by CYP2D6star10A and star2 genotypes (Kruskal-Wallis test; P = 0.37), even in those cases whose daily doses were lower than 20 mg (n=90, P=0.91). Subjects having duplicated genes (n=6) did not show significant differences of plasma concentration-dose ratio by comparison with subjects who had no duplicated genes (Mann-Whitney U-test; P = 0.80). Conclusions Gene duplication, and the common Japanese mutation CYP2D6star10A on CYP2D6 gene are not likely to be the main modulatory factors of plasma concentration of haloperidol in Japanese psychiatric subjects.