常见的p-gp(P-糖蛋白药物相互作用).ppt

施楠楠 心血管药物中P-gp介导的DDI --地高辛专题 内容 P-gp的概念、分布、作用 P-gp的底物药物与抑制药物 地高辛及胺碘酮DDI总结 4 1 2 3 不同药物通过p-gp对地高辛的影响 5 小结 P-糖蛋白的概念 Polymorphisms in Human MDR1 (P-glycoprotein): Recent Advances and Clinical Relevance Clinical Pharmacology Therapeutics 75, 13-33 (January 2004) P-糖蛋白是最先在肿瘤细胞发现的,由多药抗药基因(MDR)表达的一种ATP依赖性载体蛋白。是以140Kda的前体蛋白经糖基化后形成的分子量为170Kda的糖蛋白以表达在细胞的浆膜上。 P-糖蛋白的分布 P-蛋白在正常人体组织广泛分布。 在肠粘膜、肾小管近曲小管上皮细胞、泌胆汁肝细胞、肾上腺皮质和胰腺细胞上均有表达。另外,在血液-组织屏障的毛细血管内皮细胞、怀孕子宫内膜和胎盘、血脑屏障的毛细血管内皮细胞也有P-糖蛋白的表达。 Polymorphisms in Human MDR1 (P-glycoprotein): Recent Advances and Clinical Relevance Clinical Pharmacology Therapeutics 75, 13-33 (January 2004) P-gp tissue distribution. Efflux activity associated with P-gp would reduce intestinal drug absorption while enhancing drug elimination through the liver and kidney. At barrier sites such as the blood-brain barrier, testes, or placenta, P-gp would limit tissue exposure to potentially toxic P-gp substrate compounds. 人体各部位P-糖蛋白的作用 胃肠道、肝脏 胃肠道P-gp降低底物吸收、降低生物利用度 肠道、肝脏P-gp增加药物的非肾清除、增加随粪排泄量 肾脏、肾上腺 各屏障 肾小管上皮细胞的p-gp增加肾清除 肾上腺的p-gp对一些激素有促进作用、且受一些外源性物质影响 各屏障上的P-gp可使药物的Vd减少 Yu Dk.The contribution of P-glycoprotein to pharmacokinetic drug-drug interactions. J Clin Pharmacol.1999:39;203-1211 P-糖蛋白相关的肿瘤多耐药机制 8 刘治军等。药物不良反应杂志，2006，8（1）：33-38 10 利福平对地高辛的影响 J Clin Invest.1999,104(2)147-153 口服和静脉应用地高辛及联合利福平 时地高辛的药时曲线 After administration of rifampin, AUC of oral digoxin was significantly decreased (P 0.05). Maximal plasma levels were reduced by 58% (P 0.01), and Tmax increased from 42 to 52 minutes (P 0.05). Oral bioavailability (F) of digoxin decreased by 30.1% during rifampin therapy (P 0.05). A smaller, although still significant, change (P 0.05) was noted for the decrease of plasma AUC after intravenous administration, with digoxin’s systemic clearance increasing by 21% (P 0.05). Renal clearance of digoxin and creatinine clearance were not altered by rifampin. Cumulative urinary excretion of orally and intravenously administered digoxi