Effects of the CYP2D6*10 Allele on the Steady-State Plasma Concentrations of Aripiprazole and Its Active Metabolite, Dehydroaripiprazole, in Japanese Patients With Schizophrenia

The CYP2D6*10(*10) allele that causes decreased CYP2D6 activity is present in Asians with a high frequency of approximately 50%. We studied the effects of the *10 allele on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole. The subjects were 63 Japanese patients with schizophrenia who had only the wild-type or *10 alleles. Twenty-seven patients were homozygous for the wild-type allele, 31 were heterozygous, and five were homozygous for the *10 allele. All patients had been receiving the fixed doses of aripiprazole for at least 2 weeks. The daily doses were 24 mg (n = 40) and 12 mg (n = 23). No other drugs except biperiden and flunitrazepam were coadministered. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection. The mean ± standard deviation values of concentration/dose ratios of aripiprazole in the patients with zero, one, and two *10 alleles were 9.0 ± 2.9, 12.7 ± 4.4, and 19.0 ± 6.8 ng/mL/mg, respectively, and those values for dehydroaripiprazole were 4.9 ± 1.6, 5.9 ± 1.7, and 5.9 ± 1.9 ng/mL/mg, respectively. The respective values for the sum of aripiprazole and dehydroaripiprazole were 13.9 ± 4.3, 18.6 ± 5.9, and 24.6 ± 8.5 ng/mL/mg. The mean concentration/dose ratios of aripiprazole were significantly (P < 0.01 or P < 0.001) different among the three genotype groups. The values for the sum of aripiprazole and dehydroaripiprazole were significantly higher in patients with one (P < 0.01) and two (P < 0.001) *10 alleles compared with those with zero *10 alleles. This study suggests that the *10 allele plays an important role in controlling the steady-state plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole in Asian subjects.