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Prediction of Pharmacokinetics and Efficacy/Toxicity by Genotypes of Metabolic Enzymes

通过代谢酶基因型预测药代动力学和功效/毒性

基本信息

批准号：
07457558
负责人：
OKUMURA Katsuhiko
金额：
$ 4.74万
依托单位：
KOBE UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

项目摘要

N-acetyltransferase 2 (NAT2) and cytochrome P450 2C19 enzymes are known to exhibit a hereditarily determined polymorphism. The characterization of genetic variation at the DNA level for these enzymes has made it possible to determine an individual genotype. The common method is a polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) method using blood samples. We have developed a novel method for determining the NAT2 and CYP2C19 genotypes using genomic DNA extracted from single hairs, buccal cells and fingernail.The N-acetylation activity for procainamide, isoniazid (INH) and sulfapyridine (SP) was well correlated with NAT2 genotype in healthy volunteers study. Urinary excretion ratios of AcINH and INH in tuberculous patients and plasma concentration of AcSP and SP in ulcreative colitis also showed the same values in each NAT2 genotype as normal subjects. Therefore, NAT2 genotype is the main factor which effect on the metabolism of these drugs compared with coadministration drugs or hepatic and renal functions. Furthermore, we have first found that anti-Helicobacter pylori efficacy of omeprazole can be related to the CYP2C19 genotype, that is, the eradication effect of omeprazole with amoxicillin was highly efficient in CYP2C19 poor metabolizers, suggesting that clarithromycin or metronidazole needs not to be used for this group on the first line therapy. Genotyping by PCR-RFLP,which is a simple in vitro test, can provide a new strategy to choose an optimal regimen based upon the individual genotype.

已知N-乙酰转移酶2（NAT 2）和细胞色素P450 2C 19酶表现出遗传决定的多态性。这些酶在DNA水平上的遗传变异的表征使得确定个体基因型成为可能。常见的方法是使用血液样品的聚合酶链反应（PCR）和限制性片段长度多态性（RFLP）方法。我们建立了一种新的方法，从单个头发，颊细胞和指甲中提取的基因组DNA的NAT 2和CYP 2C 19基因型，普鲁卡因胺，异烟肼（INH）和磺胺吡啶（SP）的N-乙酰化活性与NAT 2基因型在健康志愿者的研究有很好的相关性。结核患者尿AcINH和INH排泄率及溃疡性结肠炎患者血浆AcSP和SP浓度在各NAT 2基因型中与正常人相同。因此，与联合用药或肝肾功能相比，NAT 2基因型是影响药物代谢的主要因素。此外，我们首次发现奥美拉唑的抗幽门螺杆菌疗效可能与CYP 2C 19基因型相关，即奥美拉唑与阿莫西林的根除作用在CYP 2C 19弱代谢者中非常有效，这表明克拉霉素或甲硝唑不需要用于该人群的一线治疗。PCR-RFLP基因分型是一种简单的体外检测方法，可为根据个体基因型选择最佳治疗方案提供新的策略。