Haloperidol plasma concentration in Japanese psychiatric subjects with gene duplication of CYP2D6.
OBJECTIVE
The cytochrome P-450 2D6 (CYP2D6) gene duplication/multiduplication producing an increase in enzyme activity, and the common Japanese mutation, CYP2D6*10A 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-RFLP) method was performed to identify the CYP2D6*10A and CYP2D6*2 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-RFLP 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 *1/*1, *1/*2, *1/*10A, *2/*2, *2/*10A and *10 A/*10A, respectively. Six cases (5.4%) had duplicated CYP2D6 genes. There were no significant differences of plasma concentration-dose ratio between the groups classified by CYP2D6*10A and *2 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 CYP2D6*10A on CYP2D6 gene are not likely to be the main modulatory factors of plasma concentration of haloperidol in Japanese psychiatric subjects.
Ohnuma
Tohru
T
Department of Psychiatry, Juntendo Koshigaya Hospital, 560 Fukuroyama, Koshigaya-shi Saitama, 343-0032 Japan. tohru.oonuma@nifty.ne.jp
Shibata
Nobuto
N
Matsubara
Yoichiro
Y
Arai
Heii
H
D000284:Administration, Oral; D000328:Adult; D014150:Antipsychotic Agents / Q000097:blood* / Q000627:therapeutic use; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D020440:Gene Duplication; D005838:Genotype; D006220:Haloperidol / Q000097:blood* / Q000627:therapeutic use; D006801:Humans; D007564:Japan / Q000208:ethnology; D008297:Male; D001523:Mental Disorders / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length
D014150:Antipsychotic Agents; D019389:Cytochrome P-450 CYP2D6; D006220:Haloperidol