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.Hof
2、fmeyer,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 clustered according t
3、o 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)in the duodenum.(B)Distribution
4、 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.,Pharmacogenetics 2004;Morimoto et al.,Drug M
5、etab Pharmacokinet 2004IntracellularExtracellularF73LV82AN130DR152KP155TE156GV174AD241NN432DD462GG488AD655GE667GI353TN151SP336RC485FL643FL543WTimeBlood Concentration“Normal”ActivityEnhanced ActivityDecreased Activity hydrophillic“statin”HMG-CoA reductase inhibitor not metabolized Clearance is uptake
6、 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 scrutinyPharmacogeneticsPersonalized sequencingPrecision therapiesPharmacogenomic diagnosticsomics integration
