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 (NAT2) 和细胞色素 P450 2C19 酶表现出遗传决定的多态性。这些酶在 DNA 水平上的遗传变异特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本的聚合酶链反应（PCR）和限制性片段长度多态性（RFLP）方法。我们开发了一种使用从单根毛发、颊细胞和指甲中提取的基因组 DNA 来确定 NAT2 和 CYP2C19 基因型的新方法。普鲁卡因酰胺、异烟肼 (INH) 和磺胺吡啶 (SP) 的 N-乙酰化活性与 NAT2 基因型密切相关。健康志愿者研究。结核病患者中AcINH和INH的尿排泄率以及溃疡性结肠炎中AcSP和SP的血浆浓度在各NAT2基因型中也显示出与正常受试者相同的值。因此，与合用药物相比，NAT2基因型是影响这些药物代谢或肝肾功能的主要因素。此外，我们首次发现奥美拉唑的抗幽门螺杆菌功效与CYP2C19基因型有关，即奥美拉唑联合阿莫西林对CYP2C19弱代谢者的根除效果高效，提示无需使用克拉霉素或甲硝唑为本组的一线治疗。 PCR-RFLP 基因分型是一种简单的体外测试，可以提供一种根据个体基因型选择最佳治疗方案的新策略。