Pharmacokinetics of aripiprazole, a new antipsychotic, following oral dosing in healthy adult Japanese volunteers: influence of CYP2D6 polymorphism.

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.

Novel structure of the CYP2D6 gene that confuses genotyping for the CYP2D6*5 allele.

We encountered DNA samples which showed a positive product using a long PCR-based method for the detection of CYP2D6*5, indicating deletion of the entire CYP2D6 gene, but the samples did not show a band related to CYP2D6*5 in either XbaI- or EcoRI-RFLP analysis. To achieve genotyping with accuracy, we performed a further genetic analysis to clarify the discrepancy. An unknown 1.6-kb insert was identified in a region downstream from the CYP2D6 stop codon where a specific primer was designed for long-PCR analysis for CYP2D6*5 genotyping. This finding suggested that the CYP2D6 gene might not be deleted in the samples even if a positive product was detected by the long-PCR method. Furthermore, the allelic frequency of this type was found to be approximately 0.3% (4 heterozygous/771 samples) in a Japanese population. In conclusion, we found a novel structure of the CYP2D6 gene, which might lead to incorrect genotyping for CYP2D6*5. Although the long PCR-based strategy for the detection of CYP2D6*5 has been widely used due to its usefulness and convenience, we recommend caution when adopting this method and propose re-evaluating the method for detecting CYP2D6*5.

The frequency of candidate alleles for CYP2D6 genotyping in the Japanese population with an additional respect to the -1584C to G substitution.

The -1584C/G single nucleotide polymorphism (SNP) in the promoter region of CYP2D6 was suggested to have the potential to influence CYP2D6 activity. In this report, we demonstrated the frequencies of -1584C to G substitution-related alleles, such as CYP2D6*2, CYP2D6*21, CYP2D6*35 and CYP2D6*41, in the Japanese population. The frequencies of CYP2D6*2, *41 and *21 were 0.102, 0.026 and 0.005, respectively. We also showed a relationship between the SNP and other common alleles, CYP2D6*4, *5, *10, *14 and *18. Interestingly, the SNP was detected in all three subjects carrying CYP2D6*14. This finding suggests the -1584G is included in the CYP2D6*14 allele, which is a null-allele characteristic to the Japanese population. This report presents practical information on CYP2D6 alleles that should be considered in the pharmacokinetic study of CYP2D6 substrates in the Japanese population.

Influence of itraconazole co-administration and CYP2D6 genotype on the pharmacokinetics of the new antipsychotic ARIPIPRAZOLE.

The results of in vitro studies indicated that ARIPIPRAZOLE, a newly developed antipsychotic, is mainly metabolized by the human cytochrome P450 isozymes CYP3A4 and CYP2D6. The objective of the present study was to investigate the influence of itraconazole (hereafter referred to as ITZ) co-administration (CYP3A4 inhibition) on the pharmacokinetics of ARIPIPRAZOLE administered to 24 healthy adult male volunteers in a fasting condition. The influence of CYP3A4 inhibition was also examined by CYP2D6 genotype. All subjects were administered a single oral dose of ARIPIPRAZOLE alone in Period I and a single oral dose of ARIPIPRAZOLE following administration of ITZ at 100 mg/day for 7 consecutive days in Period II. The pharmacokinetic parameters of ARIPIPRAZOLE and its main metabolite OPC-14857 were determined. Co-administration of ITZ increased the Cmax, AUC336 hr, and t1/2,z of ARIPIPRAZOLE and OPC-14857 by 19.4%, 48.0%, and 18.6% and by 18.6%, 38.8%, and 53.4%, respectively. By co-administration of ITZ, the CL/F of ARIPIPRAZOLE in extensive metabolizers was decreased by 26.6%, with an even greater decrease (47.3%) in intermediate metabolizers. For the co-administration period, the CL/F of ARIPIPRAZOLE in intermediate metabolizers was about half of that in extensive metabolizers. For Cmax, there was no significant difference between extensive metabolizers and intermediate metabolizers, and the percent change by co-administration of ITZ was less than 20% in both extensive metabolizers and intermediate metabolizers. For OPC-14857, the t(max) in intermediate metabolizers was longer than that in extensive metabolizers, with the difference being amplified by co-administration of ITZ. The AUC336 hr showed similar increases by co-administration of ITZ in all genotypes. The urinary 6beta-hydroxycortisol/cortisol concentration ratio following ITZ administration for 7 consecutive days was about half of that before the start of ITZ administration, indicating that CYP3A4 metabolic activity was inhibited by administration of ITZ. The influence of CYP3A4 inhibition on the pharmacokinetics of ARIPIPRAZOLE was not considered to be clinically significant. On the other hand, definite differences in pharmacokinetics were observed between CYP2D6 genotypes.

Impact of CYP2D6*10 on mexiletine pharmacokinetics in healthy adult volunteers.

OBJECTIVE: In vitro studies with human liver microsomes have suggested that the oxidative conversion of mexiletine (MX) to its metabolites is catalyzed by CYP2D6 and is significantly impaired in microsomes with the CYP2D6*10/*10 genotype. Therefore, we examined the influence of the CYP2D6*10 allele on MX pharmacokinetics in Japanese subjects. METHODS: Subjects with CYP2D6*1/*1 (group *1/*1; n=5), CYP2D6*10/*10 (group *10/*10; n=6) and CYP2D6*5/*10 (group *5/*10; n=4) genotypes received a single 200-mg dose of MX. Plasma and urinary levels of MX and its metabolites ( p-hydroxymexiletine (PHM), hydroxymethylmexiletine (HMM) and N-hydroxymexiletine (NHM)) were determined by means of high-performance liquid chromatography. RESULTS: Mean area under the concentration-time curve (AUC) and t(1/2) of MX were significantly ( P<0.05) higher in the CYP2D6*10/*5 group (AUC 11.23+/-3.05 micro g.h/ml; t(1/2) 15.5+/-3.2 h) than in the CYP2D6*1/*1 (AUC 5.53+/-1.01 micro g.h/ml; t(1/2) 8.1+/-1.6 h) and CYP2D6*10/*10 (AUC 7.32+/-2.36 micro g.h/ml; t(1/2) 10.8+/-2.8 h) groups, but there was no significant difference between the CYP2D6*1/*1 and CYP2D6*10/*10 groups. The maximum plasma concentration of MX was not significantly different among the three groups. The values of urinary excretion of PHM and HMM in the CYP2D6*1/*1 group were significantly ( P<0.05) higher than those in the CYP2D6*10/*10 and CYP2D6*5/*10 groups, but there was no significant difference in that of NHM among the three groups. Clearance of MX in the CYP2D6*5/*10 subjects was comparable to that in the poor metabolizers described previously. CONCLUSION: The present findings demonstrated that carriers of the CYP2D6*10 allele showed a decreased clearance of MX. Subjects with CYP2D6*5/ *10 showed significantly ( P<0.05) increased plasma levels of MX, and homozygotes for CYP2D6*10 also showed an increase, although to a lesser extent. Thus, the CYP2D6*10 allele plays an important role in MX pharmacokinetics.

Novel detection assay by PCR-RFLP and frequency of the CYP3A5 SNPs, CYP3A5*3 and *6, in a Japanese population.

In this study, we established useful and reliable methods for the direct detection of the variants of CYP3A5 gene by polymerase chain reaction (PCR) and DdeI restriction analysis. The frequency of CYP3A5 related SNPs in 200 healthy Japanese male subjects was determined. The homozygous wild-type (*1/*1) frequency was 7.0% (14/200), the heterozygous (*1/*3) frequency was 32.5% (65/200) and the homozygous mutant-type (*3/*3) frequency was 60.5% (121/200). The *6 allele was not detected in any of the Japanese individuals. This result suggests that an estimated 40% of the Japanese express relatively high levels of metabolically active CYP3A5 protein. The proposed detection assays are useful for screening the CYP3A5 related SNPs in pharmacogenetic research.