药物基因组学的原理与应用

1、2.application of genome science (genomics) to the study of human variability in drug response.3.study of genes responsible for the variability in individual responses to drugsnon-clinical approaches to assign function of interesting genes identified based on snps or dna chip based genomic analysis.h

2、offmeyer, s. et al. (2000) proc. natl. acad. sci. usa 97, 3473-3478fig. 3. correlation of the exon 26 snp with mdr-1 expression. the mdr-phenotype (expression and activity) of 21 volunteers and patients was determined by western blot analyses. box plot shows the distribution of mdr-1 expression clus

3、tered according to the mdr-1 genotype at the relevant exon 26 snphoffmeyer, s. et al. (2000) proc. natl. acad. sci. usa 97, 3473-3478fig. 4. mdr-1 expression and pgp in vivo activity after rifampin induction. mdr-1 genotype in exon 26 and distribution of rifampin-induced p-gp protein expression (a)

4、in the duodenum. (b) distribution of plasma levels of digoxin after rifampin induction. the plasma levels of digoxin area under the curve, ghl-1 (auc) are inversely proportional to p-gp activity in the duodenum. tirona et al., jbc 2001; nozawa et al., jpet 2002; nishizato et al., 2003; niemi et al.,

5、 pharmacogenetics 2004; morimoto et al., drug metab pharmacokinet 2004intracellularextracellularf73lv82an130dr152kp155te156gv174ad241nn432dd462gg488ad655ge667gi353tn151sp336rc485fl643fl543wtimeblood concentration“normal” activityenhanced activitydecreased activity hydrophillic “statin” hmg-coa reduc

6、tase inhibitor not metabolized clearance is uptake rate-limitednishizato et al., clin pharmacol ther 2003non-renal clearance: *1b/*1b (n = 4)2.01 0.42 l/ kg*h*1b/*15 (n = 9)1.11 0.34 l/ kg*h*15/*15 (n = 1) 0.29 l/ kg*h1990s2000sbeyondlinkage studiessequencingcandidate gene association studieslarge scale snp detectionwhole genome association studiesregulatory scrutinyphar