课件：抗癫痫药遗传药理学研究进展.ppt

抗癫痫药遗传药理学研究进展,Differential drug efficacy,Same symptoms Same findings Same disease (?),Same Drug.,Different Effects,?,Genetic Differences,Possible Reasons: Non-Compliance Drug-drug interactions Chance Or.,SNP,Polymorphisms Affect Drug Handling and Drug Targets,Genetic Polymorphism,Pharmacokinetics,Pharmacodynamics,Receptors Ion Channels Enzymes,Metabolism Transporters Protein Binding,Normal Population Distribution,.,10,5,0,0,10,15,20,Enzyme activities, Units/ml,Percent of subjects per 0.5 Units/ml of activity,Genetic polymorphism of drug metabolizing enzymes,.,10,5,0,0,5,10,15,20,Enzyme activities, Units/ml,Percent of subjects per 0.5 Units/ml of activity,Slight adverse effects,Severe adverse effects,Product Function MDR1/ABCB1 P-glycoprotein Transmembrane transport SCN1A 1 subunit sodium channel Movement of sodium ions cross membrane GABBR1 Gamma-aminobutyric acid receptor B Membrane receptor GABA-B TNF Subunit of tumour necrosis factor Associated with the inflammatory pathway HLA HLA Associated with immune response. CYP3A Cytochrome p450 enzyme Associated with hydroxylation CYP2C19 Cytochrome p450 enzyme Associated with hydroxylation CYP2C9 Cytochrome p450 enzyme Omega oxidation pathway CYP2A6 Cytochrome p450 enzyme Associated with oxidation MRP Multidrug resistance-associated protein Transmembrane transport OCTN2 Organic cation transport protein Transmembrane transport UGT 1A6 Uridine diphosphate glycosyltransferase Associated with glucuronidation pathway CYP1A2 Cytochrome p450 enzyme Associated with hydroxylation CYP2D6 Cytochrome p450 enzyme Associated with hydroxylation CYP2C8 Cytochrome p450 enzyme Associated with hydroxylation PXR Pregnane X receptor Associated with indirect metabolism in hydroxylation pathway PRNP Cellular prion protein Associated with neuron protection,Canditated Genes associated with pharmacogenetics of antiepileptic drugs,Drug transporters,pharmacogenetics,40%-50%,Drug-resistance Epilepsy,Model of the proposed role of cell specific MDR1 expression in epileptic brain,Immunohistochemical detection of MDR1 expression in human drug-refractory epileptic brain.,BMC Med. 2004; 2: 37,MDR1 expression and drug-resistance epilepsy,C3435T,Schematic representation of the multidrug resistance-1 (MDR1) gene and putative protein secondary structure.,MDR1 polymorphism and drug-resistance epilepsy,N Engl J Med 2003;348:1442-8.,Summary of Genotype and Phenotype Data Total Phenotype No. MDR1 3435 Genotype CC CT TT no. (%) Drug-resistant epilepsy 200 55 (27.5) 106 (53.0) 39 (19.5) Drug-responsive epilepsy 115 18 (15.7) 63 (54.8) 34 (29.6) Control 200 37 (18.5) 116 (58.0) 47 (23.5 For all 315 patients with epilepsy, patients with drug-resistant epilepsy were more likely than those with drug-responsive epilepsy to have the CC genotype than the TT genotype (x2=7.65, P=0.006).,MDR1 polymorphism and drug-resistance epilepsy,Compounds Time Wild-Type S467C Mutant min l/mg protein L-3HCarnitine 3 884.2 13.94 (100) 102.8 1.20 (9.9)* 3HAcetyl-carnitine 5 597.8 7.60 (100) 103.9 5.38 (13.5)* 14CTEA30 30 46.5 0.99 (100) 48.1 1.30 (104.8) 3HPyrilamine 5 993.5 9.95 (100) 873.9 4.42 (75.0)* 3HQuinidine 5 1524.5 23.30 (100) 1446.5 21.20 (84.3) 3HVerapami l5 2539.9 36.43 (100) 2540.1 36.81 (103.0) * Significantly different from the uptake by wild-type OCTN2 by Students t test (p 0.05).,Uptake of carnitine and organic cations by HEK293 cells expressing wild-type and S467C-mutant OCTN2,Pharmacology 2002, 302: 1286-1294,Verapamil Started Jan 03,Date of Hospitalization,Days Since Prior Hospitalization,Use of Verapamil as a Petential P-Glycoprotein Inhibitor in a Patient With Refractor Epilepsy,The Annals of Pharmacotherapy 2004,38:1631-4,Drug metabolism,Enzymes associated with major metabolic pathways Carbamazepine CYP3A4, CYP1A2, CYP2A6, CYP2C8, CYP2C19, CYP2D6, UGT1A6, UBG2B Valproic acid 50% by UGT, CYP2C9, CYP2C19 Phenytoin CYP2C9, CYP2C19, UGT Phenobarbital CYP2C9, CYP2C19 Primidone CYP2C9, CYP2C19, Gabapentin 95% excreted unchanged by kidney, rest by transaminase and vitamin B6 Tiagabine CYP3A4, UGT Topiramate 80% excreted unchanged by kidney, rest CYP2C9, CYP2C19 Felbamate CYP2E1, CYP3A4, CYP2C19 Lamotrigine More than 70% UGT1A4, 10% excreted unchanged *Alteration in any enzyme important in metabolism can alter the metabolite population formed affecting efficacy and adverse event profile,Enzymes associated with major metabolic pathways *,Genotype n (%) Mean dose (mg dd) Mean oncentration (range) (mg/l) (range) Total 60 253 15.7 CYP2C9*1/*1 37 (62%) 287 (75425) 15.8 (2.236.4) CYP2C9*1/*2 9 (15%) 201 (150225)* 16.1 (9.031.2) CYP2C9*1/*3 9 (15%) 196 (150275)* 13.8 (5.118.2) CYP2C9*2/*3 2 (3%) 175 (150200)* 20.4 (12.827.9) CYP2C9*2/*2 3 (5%) 217 (175275)* 14.0 (10.617.6) *P 0.01 versus CYP2C9*1/*1,CYP2C9 genotype distribution and mean phenytoin maintenance Dose/mean phenytoin steady-state serum concentration per enotype,Pharmacogenetics 2001, 11:287-291,Genotype n (%) Mean dose (mg dd) (range) Total 36 260 CYP2C9*1/*1 19 (53%) 314 (200425) CYP2C9*1/*2 6 (17%) 193 (150225)* CYP2C9*1/*3 7 (19%) 202 (150275)* CYP2C9*2/*3 1 (3%) 150* CYP2C9*2/*2 3 (8%) 217 (175275)* *P 0.01 versus CYP2C9*1/*1,CYP2C9 genotype and mean phenytoin maintenance dose,Pharmacogenetics 2001, 11:287-291,Group CYP2C9 CYP2C19 No. Dose(mg/day/kg) Css(ug/ml) Css/dose G1 *1/*1 *1/*1 52 3.581.48 6.64.8 1.70.8 G2 *1/*1 *1/*2 (47) 64 3.501.33 9.17.3 2.31.2a *1/*3 (17) G3 *1/*1 *2/*2 (7) 15 2.951.36 7.15.6 2.20.9 *3/*3 (3) *2/*3 (5) G4 *1/*3 *1/*1 3 2.090.17 4.72.0 2.20.8 *1/*2 *1/*2 *1, wild-typed allele a Compared with G1 groupe, p=0.018.,CYP2C9/19 genotypes,the daily doses and serum concentrations of phenytoin in 134 patients with epilepsy,Epilepsy 1998,39(12):1317-23,Pharmacogenetics 2001, 11:803-808,CYP2C9*6 and phenytoin metabolism (1),Phenytoin plasma concentration versus time profile in the study subject () and expected concentrations in a CYP2C9 extensive metabolizer ().,Pharmacogenetics 2001, 11:803-808,CYP2C9*6 and phenytoin metabolism (2),Actual and expected plasma phenytoin concentrations over the course of 41 days with day 1 as the day of presentation with phenytoin toxicity,Schematic depiction of CYP2C9 818delA allele genotyping test. Includes specific PCR amplification of exon 5 and restriction map of Mnl I sites. A. CYP2C9*1, *2 or *3. B. CYP2C9 818del A.,818del A,CYP2C9*6 allele,Pharmacogenetics 2001, 11:803-808,818del A,CYP2C9 818del A genotyping test,Pharmacogenetics 2001, 11:803-808,UGT1A6 polymorphism and Valporate metabolism,JPET,2005,313:1340-6,End-organ targets,Schematic of SCN1A,Neuronal Sodium-Channel a1-Subunit Mutations in Generalized Epilepsy with Febrile Seizures Plus(GEFS+),Am. J. Hum. Genet. 2001, 68:859865,X: D188V,An Australian family with GEFS+,Am. J. Hum. Genet. 2001, 68:859865,Y:V1353L,Am. J. Hum. Genet. 2001, 68:859865,An Ashkenazi family with GEFS+,Mutation W1204R, cosegregating with disease in a family with GEFS+. A, Family with GEFS+, with 13 individuals from four generations. Six individuals were classified as affected. DNA was obtained from five affected and three unaffected family members. CSGE analysis of exon 18 of SCN1A identified a unique pattern in the proband (arrow). The same pattern as observed in the