Establishment of The Effective and Safe Anticoagulation Therapy for Japanese Patients

为日本患者建立有效且安全的抗凝治疗

基本信息

批准号：
12670703
负责人：
TAKAHASHI Harumi
金额：
$ 2.05万
依托单位：
MEIJI PHARMACEUTICAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

To investigate the population differences in the metabolic activity of cytochrome P450 (CYP) 2C9 between genotypically-matched Caucasians and Japanese using the unbound oral clearance (CLpo,u) of (S)-warfarin as an in vivo probe.Ninety Japanese and 47 Caucasian patients on maintenance warfarin therapy were studied. Steady-state plasma unbound concentrations (Cu) of (S)-warfarin were measured by a chiral HPLC method coupled with ultrafiltration techniques. CLpo,u for (S)-warfarin and the formation clearance (CLm) of (S)-7-hydroxywarfarin were determined. Genotyping of CYP2C9 was performed with a polymerase chain reaction method for 6 distinct alleles (CYP2C9^*1, CYP2C9^*2, CYP2C9^*3, CYP2C9^*4, CYP2C9^*5 and a T/C transition in intron 2).The frequency distribution of CLpo,u for (S)-warfarin obtained from Japanese was shifted towards higher values as compared to that in Caucasians. Japanese had lower allelic frequencies for the 5 variants than Caucasians. When inter-population comparison … More s of CYP2C9 activity were made for genotype-matched subjects, Japanese with the homozygous CYP2C9^*1 (wild-type) genotype (n = 85) had significantly (p<0.01) greater median values for CLpo,u and CLm than the Caucasians with the corresponding genotype (n = 26) : 10.4 vs 4.25 ml/min/kg and 0.015 vs 0.010 ml/min/kg, respectively. In addition, heterozygous Japanese for the CYP2C9^*3 genotype (n = 4) showed a significantly (p<0.05) reduced CLpo,u for (S)-warfarin by 63 % as compared with Japanese possessing the homozygous CYP2C9^*1 genotype. By contrast, no significant differences were observed in this parameter among the Caucasian with the homozygous CYP2C9^*1 genotype and those with heterozygous CYP2C9^*2 or CYP2C9^*3 genotypes.These findings indicate that inter-population differences in the frequencies of known variant CYP2C9 alleles account only in part for the variability observed in in vivo CYP2C9 activity in different populations. Additionally, a gene-dose effect of defective CYP2C9 alleles on the in vivo CYP2C9 activity is evident in Japanese but not in Caucasians. Further studies are required to identify concealed factor(s) (e.g., transcriptional regulation) responsible for the large intra- and inter-population variability in CYP2C9 activity. Less

调查基因型P450（CYP）2C9在基因型匹配的高加索人和日本日本之间的代谢活性中的人口差异，使用（s） - 瓦尔法林的未结合的口服清除（CLPO，U）作为体内探测。通过手性HPLC方法与超滤技术相结合，测量了（S） - 华尔法林的稳态血浆未结合浓度（CU）。确定了（s） - 瓦尔法林的clpo，u和（s）-7-羟基沃尔法林的形成清除率（CLM）。用聚合酶链反应方法进行6个不同等位基因（CYP2C9^*1，CYP2C9^*2，CYP2C9^*3，CYP2C9^*4，CYP2C9^*4，CYP2C9^*5，cyp2c9^*3，cyp2c9^*3，cyp2c9^*3，cyp2c9^*3，cyp2c9^*5和a t/c转变的频率与clpo的频率相比，u for（s）在高加索人中。与高加索人相比，日本的5种变体频率较低。当人群间比较时……对基因型匹配的受试者进行了更多的CYP2C9活性，日语具有纯合的CYP2C9^*1（野生型）基因型（n = 85）具有显着的（p <0.01）的中位数（p <0.01）的CLPO，u和clm的中间值，u和clms u and u and clm and clm and clm and clm and clm and clm and clm and clm and clm and clm and clm and clm and clm and clm and clm and clm and clm and clm and clm and clm and clm and clm afts u and。分别为0.015和0.010 mL/min/kg。此外，与拥有纯合子CYP2C9^*1基因型的日语相比，CYP2C9^*3基因型（n = 4）的杂合日语显示出明显的（p <0.05）降低了CLPO，U的CLPO，U的u，u降低了63％。相反，在高加索人中，与纯合CYP2C9^*1基因型以及具有杂合的CYP2C9^*2或CYP2C9^*3基因型的高加索人之间未观察到显着差异。这些发现表明，这些发现表明，这些发现仅在已知的变异cip2c cyp2c cyp2c9 allelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelelel中差异中的差异CYP2C9活性在不同人群中。此外，有缺陷的CYP2C9等位基因对体内CYP2C9活性的基因剂量作用是日语，但在白种人中不是证据。需要进一步的研究来识别导致CYP2C9活性中较大人口内和人口间变化的隐蔽因子（例如，转录调节）。较少的