消化性溃疡疾病遗传药理学.ppt

中南大学临床药理研究所Institute of Clinical Pharmacology Central South University,个体化药物治疗系列讲座,消化性溃疡疾病遗传药理学,报告人:李智,概述,消化性溃疡（Peptic ulcer)上消化道由于自身消化作用产生的深达黏膜下的损伤。绝大多数位于胃和十二指肠，其中以十二指肠溃疡居多。,发病机制,损伤因素包括：胃酸、胃蛋白酶、幽门螺杆菌、非甾体类消炎药、乙醇、吸烟、胆汁反流及炎性介质等防御因素包括：胃黏膜-黏液屏障、重碳酸盐、磷脂、黏膜血流、细胞更新、前列腺素和表皮生长因子等。,损伤因素与防御因素之间的失衡导致溃疡,发病机制,1910年Schwartz提出：没有胃酸就没有溃疡 1982年Warren和Marshow发现幽门螺杆菌后，有人提出：没有幽门螺杆菌就没有溃疡；没有 幽门螺杆菌就没有溃疡复发,至病因素,与胃液中胃酸及胃蛋白酶的消化作用有关 乙醇或乙酰水杨酸等抗炎药物破坏胃肠 黏膜屏障 幽门螺杆菌感染 长期精神过度紧张、焦虑不安等精神因 素亦可促使溃疡形成,消化性溃疡分类,HP相关性溃疡 幽门螺杆菌(Helicobacter Pylori，HP)相关性溃疡 NSAID相关性溃疡 非甾体抗炎药(Non-steroidal Anti-inflamatory Drug，NSAID)引起的溃疡 非 H.P、非NSAID相关性溃疡 促胃液素瘤，胃、十二指肠克罗恩病。,常用治疗药物,抗酸药 三硅酸镁、氢氧化铝、氢氧化铝凝胶、氧化 镁、碳酸氢钠、重质碳酸钠、铝酸铋、枸橼 酸铋钾及碳酸钙等传统抗酸药,常用治疗药物,H2受体拮抗剂 西咪替丁、雷尼替丁、法莫替丁、尼札替丁、尼沙替丁等 质子泵抑制剂（proton pump inhibitors PPI）奥美拉唑、兰索拉唑、泮托拉唑、雷贝拉唑等,常用治疗药物,抗生素类药物 阿莫西林、克拉霉素、甲硝唑、呋喃唑 酮、左氧氟沙星等 其它药物 胶体次原酸铋、前列腺素衍生物、硫糖铝,治疗方案,目前治疗消化性溃疡的疗法是在传统的酸中和、酸抑制、保护并促进溃疡面愈合、调节胃动力等基础上与抗菌药物联用 以铋剂为主的三联疗法 以PPI为主的三联疗法,临床上消化性溃疡病药物治疗存在个体差异现象。机制：决定药物作用的药物代谢酶、转运体和受体（药物作用靶点）的功能因遗传变异而发生改变，导致药物体内浓度和药物受体反应性不同。,PPI遗传药理学,CYP2C19基因多态性对基于PPI药物治疗的影响,Parietal cell,PPI,Gastrin,Acetylcholine,Histamine,PPI抑制胃酸分泌机制,The European H.Pylori Study Group(EHPSG)guidelines recommend a 1-week,first-line treatment with a proton pump inhibitor(PPI)plus two antibiotics(amoxicillin and either clarithromycin or metronidazole),PPI是根除H.pylori治疗中的关键药物,PPI通过升高胃内pH 使抗生素更稳定和提高其生物利用度胃内pH 升高，使H.pylori 处于生长活动期，提高H.pylori 对抗生素（如：amoxicillin）。PPI抑制胃酸分泌可提高抗生素局部药物浓度。PPIs 有一定的抗H.pylori 活性。,PPI药物代谢酶,PPI主要通过CYP2C19代谢,CYP2C19基因多态性,目前已发现19种单碱基突变，命名为CYP2C19*2-*20。常见突变基因为：东方人-CYP2C19*2和*3 白种人-CYP2C19*2,CYP2C19表型与基因型,根据对omeprazole代谢能力分为：快代谢型 rapid extensive metabolizer RM 中强代谢型 intermediate metabolizer IM 弱代谢型 poor metabolizer PM根据基因突变情况基因型分为：wt/wt、wt/m、m/m,CYP2C19基因多态性对PPI药代动力学影响(omeprazole),CYP2C19基因多态性对PPI药代动力学影响(omeprazole),CYP2C19基因多态性对PPI药代动力学影响(omeprazole、lansoprazole、rabeprazole),CYP2C19基因多态性对PPI药代动力学影响(omeprazole、lansoprazole、rabeprazole),CYP2C19基因多态性对Omeprazole抑制胃酸分泌的影响,Profiles of intragastric pH values(A)and the 24-hour mean intragastric pHs(B)as a function of CYP2C19 genotype status for 20 mg of omeprazole(OPZ)dosing.,Omeprazole AUC与胃内pH值相关性,Intragastric pH profiles for 20 mg of omeprazole(OPZ),30 mg of lansoprazole(LPZ),or 20 mg of rabeprazole(RPZ)dosing for 8 days as a function of CYP2C19 genotype status.,CYP2C19基因多态性对PPI抑制胃酸分泌的影响(OPZ,LPZ,RPZ),胃溃疡治愈率与LPZ血浆浓度,CYP2C19不同表型与LPZ胃溃疡治愈率,CYP2C19不同表型对基于PPI根除H.pylori疗效的影响（二联用药）,Cure rates for H.pylori infection by dual therapy with 20 mg of omeprazole plus 2000 mg of amoxicillin for 2 weeks(OPZWAMPC)and the dual therapy with 20 mg of rabeprazole plus 1500 mg of amoxicillin for 2 weeks(RPZWAMPC)as a function of the CYP2C19 genotype groups.,CYP2C19不同表型对基于PPI根除H.pylori疗效的影响（三联用药）,H.pylori eradication rates achieved by the triple opz or lpz/amoxicillin/clarithromycin therapy in the total and for the different CYP2C19genotype groups.Bars indicates 95%confidence intervals(95%CI).,Frequencies of CYP2C19 genotypes in patients with eradication and non-eradication of H.pylori infection by triple opz or lpz/amoxicillin/clarithromycin therapy.,胃溃疡治愈与治疗失败病人中CYP2C19不同基因型频率（三联用药）,CYP2C19不同基因型对不同剂量PPI抑制胃酸分泌的影响,Median nocturnal intragastric pH values with different dosing regimens of rabeprazole in 3 CYP2C19 genotype groups.In homozygous EMs the median nocturnal pH attained by 10 mg 4 times daily was highest.The median nocturnal pH values attained by divided-dose regimens in heterozygous EMs and with 20 mg once daily in PMs were sufficiently elevated.,RMs基因型病人中相同剂量不同给药次数对RPZ抑制胃酸分泌的影响,RM（CYP2C19）病人高剂量PPIs的治愈率,Cure rates of H.pylori infection by treatment with highdoses of a PPI plus amoxicillin,PPper protocol analysis,OPZomeprazole,LPZlansoprazole,RPZrabeprazole,PPIs与Clarithromycin药物相互作用,Mean(SE)plasma levels of omeprazole(OPZ)in the RM,IM,and PM groups with and without clarithromycin(CAM).,Mean SE plasma concentrationtime curves of clarithromycin and AUC values for clarithromycin in the three different genotype groups.Significant differences in plasma clarithromycin levels were observed among the three different CYP2C19 genotype groups.,PPIs与Clarithromycin药物相互作用,小结,不同CYP2C19基因型可显著影响PPIs：血药浓度胃酸分泌溃疡病治愈率结论：在快代谢型患者中，提高PPI的剂量可 显著提高溃疡病治愈率。,其他遗传因素对消化道溃疡病药物治疗的影响,CYP3A4基因多态性与clarithromycin、Metronidazole,Clarithromycin、Metronidazole 主要经CYP3A4代谢（图表说明）Drug Metabolism and Pharmacokinetics Vol.18(2003),No.2 pp.104-113 Ann Pharmacother 1996;30:3646.CYP3A4基因多态性影响clarithromycin、Metronidazole药效？,CYP2C19和CYP3A4基因多态性对三联疗法治愈率的影响,genetic polymorphism of CYP2C19 and CYP3A4 influences the efficacy of H.pylori eradication therapy with a PPI(omeprazole,pantoprazole,and lansoprazole)and amoxicillin or clarithromycin,CYP2C19和MDR1基因多态性对三联疗法治愈率的影响,Allele frequencies for CYP2C19 and MDR1 in subjects enrolled the study(n=70).CYP2C19*1 wild-type,CYP2C19*2 mutation in exon 5,C C position 3435 of MDR1 gene,T T position 3435 of MDR1 gene,OAC omeprazole,amoxicillin,and clarithromycin,PAM pantoprazole,amoxicillin,and metronidazole,细胞因子基因多态性对H.pylori根除率的影响,IL-1B、IL-1RN、IL-10、TNF-A影响H.P根除效果。（图表）,H.Pylori耐药与基因突变,H.Pylori耐药与基因突变,H.Pylori耐药与基因突变,H.Pylori耐药与基因突变,Cimetidine、ranitidine与FMO3,FMO3介绍,Cimetidine、ranitidine与FMO3,Cimetidine、ranitidine与FMO3,Cimetidine、ranitidine与FMO3,Cimetidine、ranitidine与FMO3,Thanks,