藥物基因組學的原理與應(yīng)用學習教案

1、會計學1第一頁，共30頁。第1頁/共30頁第二頁，共30頁。第2頁/共30頁第三頁，共30頁。第3頁/共30頁第四頁，共30頁。第4頁/共30頁第五頁，共30頁。第5頁/共30頁第六頁，共30頁。第6頁/共30頁第七頁，共30頁。第7頁/共30頁第八頁，共30頁。第8頁/共30頁第九頁，共30頁。第9頁/共30頁第十頁，共30頁。第10頁/共30頁第十一頁，共30頁。2.Application of genome science (genomics) to the study of human variability in drug response.3.Study of genes resp

2、onsible for the variability in individual responses to drugs第11頁/共30頁第十二頁，共30頁。第12頁/共30頁第十三頁，共30頁。第13頁/共30頁第十四頁，共30頁。第14頁/共30頁第十五頁，共30頁。第15頁/共30頁第十六頁，共30頁。Non-clinical approaches to assign function of interesting genes identified based on SNPs or DNA chip based genomic analysis.第16頁/共30頁第十七頁，共30頁。第1

3、7頁/共30頁第十八頁，共30頁。第18頁/共30頁第十九頁，共30頁。第19頁/共30頁第二十頁，共30頁。第20頁/共30頁第二十一頁，共30頁。Hoffmeyer, 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 Wes

4、tern blot analyses. Box plot shows the distribution of MDR-1 expression clustered according to the MDR-1 genotype at the relevant exon 26 SNP第21頁/共30頁第二十二頁，共30頁。Hoffmeyer, S. et al. (2000) Proc. Natl. Acad. Sci. USA 97, 3473-3478Fig. 4. MDR-1 expression and PGP in vivo activity after rifampin induct

5、ion. MDR-1 genotype in exon 26 and distribution of rifampin-induced P-GP protein expression (A) 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 du

6、odenum. 第22頁/共30頁第二十三頁，共30頁。Tirona et al., JBC 2001; Nozawa et al., JPET 2002; Nishizato et al., 2003; Niemi et al., Pharmacogenetics 2004; Morimoto et al., Drug Metab Pharmacokinet 2004IntracellularExtracellularF73LV82AN130DR152KP155TE156GV174AD241NN432DD462GG488AD655GE667GI353TN151SP336RC485FL643F

7、L543W第23頁/共30頁第二十四頁，共30頁。TimeBlood Concentration“Normal” ActivityEnhanced ActivityDecreased Activity hydrophillic “statin” HMG-CoA reductase inhibitor not metabolized Clearance is uptake rate-limited第24頁/共30頁第二十五頁，共30頁。第25頁/共30頁第二十六頁，共30頁。Nishizato et al., Clin Pharmacol Ther 2003Non-renal clearance

8、: *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*h第26頁/共30頁第二十七頁，共30頁。第27頁/共30頁第二十八頁，共30頁。1990s2000sBeyondLinkage studiesSequencingCandidate gene association studiesLarge scale SNP detectionWhole genome association studiesRegulatory scrutinyPharmacogenetic