What will be the role of pharmacogenetics in evaluating drug safety and minimising adverse effects?
What will be the role of pharmacogenetics in evaluating drug safety and minimising adverse effects?
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DOI：
10.2165/00002018-200124020-00001
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发表时间：
2001-01-01
期刊：
影响因子：
4.2
通讯作者：
Kalow, W
中科院分区：
文献类型：
--
作者：
Ozdemir, V;Shear, NH;Kalow, W
在美国，药物不良反应（adr）排在第四位到第六位，排在肺炎和糖尿病之前。严重和致命的药物不良反应发生率高的一个重要原因是，现有的药物开发模式没有提供足够的信息，说明新的候选治疗药物的药代动力学和药效学的显著差异的机制来源，从而阻碍了针对个体患者的治疗。药物遗传学是研究人与人之间药物反应差异的遗传基础。传统上，药物遗传学研究的重点是由单一基因作用引起的异常和极端的药物反应。人类基因组计划和分子遗传学的最新进展现在为研究人类基因组中的所有基因提供了前所未有的机会，包括药物代谢基因、药物靶点和受体后第二信使机制，以及与药物安全性和有效性的变异性有关的基因。除了基因组中的序列变异外，在药物治疗前和治疗过程中对差异调节的mRNA物种进行高通量和全基因组转录谱分析将成为揭示药物作用新机制的重要工具。药物遗传学指导的药物发现和开发代表了一种与传统方法的背离，传统方法是针对广泛的患者群体销售药物，而不是针对药物可能更有效的小群体患者。药物遗传学提供了一个合理的框架，以尽量减少药物治疗和临床试验结果的不确定性，从而应显著降低药物毒性的风险。
In the US, adverse drug reactions (ADRs) rank between the fourth to sixth leading cause of death, ahead of pneumonia and diabetes mellitus. An important reason for the high incidence of serious and fatal ADRs is that the existing drug development paradigms do not generate adequate information on the mechanistic sources of marked variability in pharmacokinetics and pharmacodynamics of new therapeutic candidates, precluding treatments from being tailored for individual patients.Pharmacogenetics is the study of the hereditary basis of person-to-person variations in drug response. The focus of pharmacogenetic investigations has traditionally been unusual and extreme drug responses resulting from a single gene effect. The Human Genome Project and recent advancements in molecular genetics now present an unprecedented opportunity to study all genes in the human genome, including genes for drug metabolism, drug targets and postreceptor second messenger machinery, in relation to variability in drug safety and efficacy. In addition to sequence variations in the genome, high throughput and genome-wide transcript profiling for differentially regulated mRNA species before and during drug treatment will serve as important tools to uncover novel mechanisms of drug action. Pharmacogenetic-guided drug discovery and development represent a departure from the conventional approach which markets drugs for broad patient populations, rather than smaller groups of patients in whom drugs may work more optimally.Pharmacogenetics provides a rational framework to minimise the uncertainty in outcome of drug therapy and clinical trials and thereby should significantly reduce the risk of drug toxicity.