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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

使用(S)-华法林的未结合口服清除率(CLpo,u)作为体内探针，研究基因型匹配的白种人和日本人之间细胞色素P450 (CYP) 2C9代谢活性的人群差异。对90名日本人和47名接受华法林维持治疗的患者进行了研究。 (S)-华法林的稳态血浆非结合浓度 (Cu) 通过手性 HPLC 方法与超滤技术相结合进行测量。测定了 (S)-华法林的 CLpo,u 和 (S)-7-羟基华法林的形成清除率 (CLm)。使用聚合酶链式反应方法对 6 个不同等位基因（CYP2C9^*1、CYP2C9^*2、CYP2C9^*3、CYP2C9^*4、CYP2C9^*5 和内含子 2 中的 T/C 转换）进行 CYP2C9 基因分型。与从日本获得的 (S)-华法林相比，CLpo,u 的频率分布向更高值移动在白种人中。日本人的 5 个变体的等位基因频率低于白种人。当对基因型匹配的受试者进行人群间比较时...更多 s CYP2C9 活性，具有纯合 CYP2C9^*1（野生型）基因型 (n = 85) 的日本人的 CLpo,u 和 CLm 中值显着 (p<0.01) 高于具有相应基因型的白种人 (n = 26)：10.4 vs 4.25毫升/分钟/公斤和分别为 0.015 与 0.010 毫升/分钟/公斤。此外，与拥有纯合 CYP2C9^*1 基因型的日本人相比，CYP2C9^*3 基因型杂合的日本人 (n = 4) 显示 (S)-华法林的 CLpo,u 显着降低 (p<0.05) 63%。相比之下，在具有纯合 CYP2C9^*1 基因型的白种人和具有杂合 CYP2C9^*2 或 CYP2C9^*3 基因型的白种人中，该参数没有观察到显着差异。这些发现表明，已知变异 CYP2C9 等位基因频率的群体间差异仅部分解释了体内观察到的变异性不同人群中 CYP2C9 的活性。此外，缺陷 CYP2C9 等位基因对体内 CYP2C9 活性的基因剂量效应在日本人中很明显，但在白种人中则不然。需要进一步的研究来确定导致 CYP2C9 活性在群体内和群体间存在较大变异的隐藏因素（例如转录调控）。较少的