No abstract

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.

In this study, we tested the influence of the serotonin type 2A, 3A and 3B receptor genes (HTR2A, HTR3A, HTR3B) in addition to a polymorphism in the promoter region of the serotonin transporter (SERTPR), and investigated the different characteristics of clinical responses to paroxetine and fluvoxamine. A total of 100 Japanese patients affected by major recurrent depression were enrolled in a randomized 6-week study. The clinical response was evaluated using the Hamilton Rating Scale for Depression (HAM-D), and adverse drug reactions were assessed at each visit. Patients with the l allele of SERTPR showed a better response to SSRIs than s/s genotype carriers (p = 0.015–0.042), more significantly to fluvoxamine. The –1438G/G genotype of HTR2A was associated with a good response to SSRIs (p = 0.010–0.039), especially to fluvoxamine, and significantly with severe nausea in paroxetine-treated patients (p = 0.013). The 178C/C genotype of the HTR3A was associated with an antidepressant response (p = 0.022–0.042), and more significantly in paroxetine-treated patients (p = 0.002–0.042). These effects were independent of one another. We replicated the finding that the SERPTR polymorphism was associated with a response to SSRIs. We additionally found that HTR2A and HTR3A polymorphisms are associated with the efficacy, and the HTR2A polymorphism is also associated with adverse drug reactions. Furthermore, the effects of these polymorphisms varied from one SSRI to another and thus may depend on the characteristics of each SSRI.

CYP3A5 expression is regulated by single-nucleotide polymorphisms (SNPs). The CYP3A5 genotype might contribute to a marked interindividual variation in CYP3A-mediated metabolism of drugs. Nifedipine is a typical substrate of CYP3A4 and CYP3A5 in vitro. The aim of this study was to elucidate the influence of the CYP3A5 genotype on nifedipine disposition in healthy subjects. A single capsule containing 10 mg of nifedipine was administered to 16 healthy male Japanese subjects (eight subjects: CYP3A5*1/*3; eight subjects: CYP3A5*3/*3). Blood samples were collected to analyze the pharmacokinetics of serum nifedipine and nitropyridine metabolite (M-I). The area under the plasma concentration-time curve (AUC), the peak plasma concentration (C max ) and the terminal half-life (t 1/2 ) of nifedipine, and the ratio of the nifedipine AUC to M-I AUC showed large intragroup variations, but no significant differences between the two genotypes. Based on the present findings, the functional relevance of CYP3A5 polymorphism should be re-evaluated in clinical trials. 2 Recently, single-nucleotide polymorphisms (SNPs) were identified in intron 3 (A-G: CYP3A5*3) and exon 7 (G-A: CYP3A5*6) of the CYP3A5 gene.3 In addition, CYP3A5*5 and CYP3A5*7 were reported as a defective allele of CYP3A5, which gave a substantial impact on CYP3A5 expression. 4,5 These SNPs cause a frame-shift mutation or alternative splicing and protein truncation, and result in the absence of CYP3A5, suggesting that only people with at least one CYP3A5*1 allele express large amounts of CYP3A5 protein. Therefore, these findings suggest that polymorphic CYP3A5 expression might be one factor contributing to the marked interindividual variation observed in CYP3A-mediated metabolism of drugs.We previously reported the frequencies of CYP3A5-related SNPs in 200 healthy Japanese subjects. 6 As a result, the allele frequency of CYP3A5*3 was approximately 70%, but CYP3A5*6 was not detected in the Japanese population. Accordingly, these findings suggested that about 40% of Japanese express relatively high levels of metabolically active CYP3A5 protein.

The present study aimed to compare the effects of two currently used selective serotonin reuptake inhibitors (SSRIs) in Japan taking the individual background in 5-HTT gene-linked polymorphic region (5HTTLPR) genotype into account. Clinical responses to paroxetine and fluvoxamine were evaluated by total and cluster depressive symptoms for 81 Japanese patients who were diagnosed with major depression. Patients with the l allele had a greater percentage reduction on the total score (P=0.059) and somatic anxiety items (P=0.026) of the 21-item Hamilton Depression Rating Scale (HAM-D) score compared to s/s genotype carriers. Paroxetine was significantly more effective than fluvoxamine in the s/s carriers, as evaluated on the percentage reduction in total score (P=0.012) and core (P=0.049) HAM-D after 4 weeks of medication, but not in the l/s carriers. These findings suggest that the genetic test may be useful in investigating the efficacy of the two SSRIs, and that normalization by the 5HTTLPR genotypes may lead to improvement of the precision of comparative analysis.