Pharmacogenetics and Drug Interactions

药物遗传学和药物相互作用

基本信息

批准号：
7675135
负责人：
TIMOTHY S. TRACY
金额：
$ 42.28万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2013-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Data are accumulating to suggest that genetic variation in human drug metabolizing enzymes can profoundly affect not only the rate of drug metabolism but also the degree of drug-drug interactions observed upon concomitant drug dosing. The long term goals of this research are to understand the effects of genetic polymorphisms in P450 enzymes on susceptibility to drug- drug interactions and to develop models to predict these changes in interaction potential; quantifying these effects will improve the accuracy of clinical dosing adjustments. A major finding from the previous granting period was that CYP2C9 variants with reduced function (i.e., CYP2C9*3) exhibit altered degrees of inhibition in both an in vitro model and in an initial in vivo human clinical study of the interaction of flurbiprofen (CYP2C9 probe substrate) and fluconazole (CYP2C9 inhibitor). Implicit in this finding is the hypothesis that an interplay between fraction of drug metabolized by CYP2C9 and genotype determines the extent of drug interaction observed. This preliminary study has significant clinical importance as it suggests that individuals of differing genotypes may require different adjustments of doses upon drug co-administration and in particularly for narrow therapeutic index drugs, such as phenytoin. The current competing renewal builds upon the above findings to: a) validate an enzyme-based pharmacokinetic model that uses a genotype-specific inhibition constant (Ki) to determine the extent of the drug interaction and the impact on the fraction of drug metabolized, and b) develop an in vitro model of homozygous poor metabolism and heterozygous partial null metabolism for predicting genotype-dependent drug-drug interactions. Through enhanced understanding of the effect of genotype on interactions and development of a predictive model that utilizes both in vitro data and known metabolism characteristics of the compound of interest, drug interactions can be managed more effectively resulting in improved patient outcomes. PUBLIC HEALTH RELEVANCE: A person's genetic makeup can affect drug disposition and action, as well as the susceptibility to drug interactions. Improved understanding of these genetic changes and their effects on drug disposition will lead to improved drug therapy and better management of drug-drug interactions.

描述（由申请人提供）：数据正在积累，以表明人类药物代谢酶的遗传变异不仅会对药物代谢率产生深远影响，而且还会影响伴随药物给药的药物毒物相互作用的程度。这项研究的长期目标是了解P450酶对药物相互作用易感性的遗传多态性的影响，并开发模型以预测相互作用潜力的这些变化；量化这些效果将提高临床给药调整的准确性。从上一个授予期开始的一个主要发现是，在体外模型和最初的体内人类临床研究中，CYP2C9变体的功能降低（即CYP2C9*3）都显示出改变的抑制程度（CYP2C9 ProbeSuptrate）和Fluconazole（Cyp2c9 probtrate）和fluconazole（Cyp2c9）和氟甘油（CYP2C9）in vivo人类临床研究。在这一发现中，隐含的假设是，通过CYP2C9代谢的药物分数与基因型的相互作用决定了观察到的药物相互作用程度。这项初步研究具有重要的临床重要性，因为它表明，不同基因型的个体可能需要对药物共同给药时的剂量进行不同的调整，尤其是对于狭窄的治疗指数药物（例如苯妥英钠）。 The current competing renewal builds upon the above findings to: a) validate an enzyme-based pharmacokinetic model that uses a genotype-specific inhibition constant (Ki) to determine the extent of the drug interaction and the impact on the fraction of drug metabolized, and b) develop an in vitro model of homozygous poor metabolism and heterozygous partial null metabolism for predicting genotype-dependent药物相互作用。通过增强对基因型对相互作用的影响和利用感兴趣化合物的已知代谢特征的预测模型的相互作用和开发的影响，可以更有效地管理药物相互作用，从而改善患者的结果。公共卫生相关性：一个人的遗传构成会影响药物处置和作用，以及对药物相互作用的敏感性。对这些遗传变化及其对药物处置的影响的改善，将改善药物治疗并更好地管理药物相互作用。