title: Pharmacokinetics of aripiprazole, a new antipsychotic, following oral dosing in healthy adult Japanese volunteers: influence of CYP2D6 polymorphism.
abstract: We investigated the pharmacokinetics (PK) of aripiprazole, a newly developed antipsychotic, and its active metabolite in healthy Japanese, and the influence of CYP2D6 polymorphism on the PK of aripiprazole. Following a single oral 6 mg dose, the mean C(max), t(max), and t(1/2, z) (terminal phase half life) of aripiprazole were 31.0 ng/mL, 3.6 hr, and 61.0 hr, respectively. The t(1/2, z) in CYP2D6 IM subjects (75.2 hr) was significantly (p<0.01) longer than that in CYP2D6 EM subjects (45.8 hr), and the systemic clearance of IM subjects was approximately 60% that of EM subjects. The PK in one subject with the CYP2D6*41 homozygote was similar to that of IM subjects. In repeated oral administration, plasma concentrations of aripiprazole and active metabolite both reached a steady state by Day 14. The half-life of aripiprazole following repeated administration was similar to that following single administration, suggesting that pharmacokinetics was constant during 14-day administration. Our investigations revealed that there is no clear ethnic difference between Japanese and Western subjects in terms of mean plasma PK, while the CYP2D6*10 allele distinctive to Asian populations influences the PK of aripiprazole. Moreover, our observations suggest that the CYP2D6*41 allele significantly affects drug-metabolizing activity.
authors.affiliation: Department of Clinical Research and Development, Otsuka Pharmaceutical Co Ltd, Osaka, Japan. kubom@otsuka.jp
authors.forename: Masanori
authors.initials: M
authors.lastname: Kubo
authors.forename: Toshiko
authors.initials: T
authors.lastname: Koue
authors.forename: Hiromi
authors.initials: H
authors.lastname: Maune
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukuda
authors.forename: Junichi
authors.initials: J
authors.lastname: Azuma
mesh_terms: D000284:Administration, Oral; D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000068180:Aripiprazole; D044466:Asian People / Q000235:genetics*; D001711:Biotransformation; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D004334:Drug Administration Schedule; D006720:Homozygote; D006801:Humans; D007564:Japan; D010641:Phenotype; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D015363:Quinolones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D012016:Reference Values; D013607:Tablets
chemical_list: D014150:Antipsychotic Agents; C504128:OPC-14857; D010879:Piperazines; D015363:Quinolones; D013607:Tablets; D000068180:Aripiprazole; D019389:Cytochrome P-450 CYP2D6