【精品】藥物基因組學(xué)的原理與應(yīng)用80-在線瀏覽
2025-07-10 06:43本頁(yè)面
【正文】 e concentrations and the associated adverse reaction (headache, facial flush). Current pharmacy practice: Use family history, racial and ethnic background to identify possible adverse drug response Future pharmacy practice: Linkage of geic tests (geic markers) to prescribing ? i) Address safety concerns ? ii) Address benefit concerns ? iii) Current limitations with respect to widespread use ? a) require highthroughput screening approaches (DNA chips) ? b) robotic methods for sample preparation ? c) costeffectiveness Pharmacogenomics ? Noninherited geic traits that alter drug response or leads to a disease state (. point mutations or collection of mutations): Identify trait using molecular means (PCR analysis, DNA chips). ? SNPs: singlenucleotide polymorphisms: Variation at a single base that is found in at least 1% of the population. i) SNP Consortium: Collaboration of pharmaceutical and technology panies and academic researchers focused on identifying SNPs. million identified to date. ii) Estimates of 10 million SNPs in the human genome including noncoding regions. SNPs in noncoding regions may effect expression levels etc. iii) Important to validate a SNP in a significantly large, ethnically diverse population to determine the allele (alternative forms of a gene) population frequency. iv) Focus on SNPs in regions that code for proteins, including proteins that influence ADME (absorption, distribution, metabolism and excretion). 3. The study areas of Pharmacogenomics ? . Drug Metabolism and transport ? Multiple panies working on microarray analysis of cytochrome p450s and drug transporters to be able to predict drug metabolism in patients. In general, pharmacogenomics and pharmacogeics will initially have their largest impact on drug metabolism rather than on drug targets. . Drug targets i) Infer function based on homology with known genes (take advantage of human genome information). ii) Transgenic or knockout mice or cells (insert or remove an unknown gene and monitor organism for changes in function). iii) interference RNA or antisense agents to suppress expression of a protein associate with a particular gene iv) Mutate unknown gene and monitor organism for changes in function v) Look at population of SNPs as a function of age: SNPs that cause debilitating/fatal diseases will be observed in a smaller percentage of the population as the population ages. This is due to the individuals with those genes having a higher probability of dying at an early age. Nonclinical approaches to assign function of interesting genes identified based on SNPs or DNA chip based genomic analysis. Polygenic and Drug Response of Pgp Position and distribution of variated MDR1 gene (1) Position and distribution of variated MDR1 gene (2) Pharmacogenomics of Pgp The relationship of genotype and phenotype Hoffmeyer, S. et al. (2000) Proc. Natl. Acad. Sci. USA 97, 34733478 Fig. 3. Correlation of the exon 26 SNP with MDR1 expression. The MDRphenotype (expression and activity) of 21 volunteers and patients was determined by Western blot analyses. Box plot shows the distribution of MDR1 expression clustered according to the MDR1 genotype at the relevant exon
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