论文部分内容阅读
药物转运体在药物-药物相互作用中扮演着重要的角色,其能够影响众多药物在血浆和组织的暴露水平.本研究初步研究了卡维地洛对二甲双胍药动学的影响及其相互作用机制.大鼠单次或连续7天灌胃给药后,采用HPLC测定血浆、尿液和组织中二甲双胍浓度,Western blotting评价rOCTs和rMATEl的表达水平.单次或连续7天联合给予卡维地洛后,二甲双胍血浆和尿液浓度并未发生明显的改变,但肝肾组织浓度却显著增加.与此一致,离体肾灌流结果显示,卡维地洛能够显著增加二甲双胍在肾脏蓄积,但并未影响其尿排泄.此外,卡维地洛对肝肾rOCTs和rMATE1的表达水平无显著的改变.长期联合用药后,卡维地洛也未影响血清乳酸、尿酸和肌酐水平.这些结果表明,卡维地洛能够增加二甲双胍肝肾组织分布,产生局部的药物相互作用.“,”Drug transporters determine plasma and tissue exposure of a broad variety of drugs and play a critical role in drug-drug interaction (DDI).In the present study,we aimed to investigate the effects of carvedilol on pharmacokinetics of metformin as well as the mechanism of their interaction.Results showed that plasma concentration of metformin was not significantly altered after single or 7-day co-administration of carvedilol,and the urinary excretion of metformin was also not influenced by carvedilol.However,the concentration of metformin in the liver and kidney was markedly elevated.Similarly,carvedilol did not affect the renal elimination of metformin,but increased renal concentration in isolated kidney perfusion.On the other hand,carvedilol treatment did not affect the expressions ofrOCTs and rMATE1 in the liver and kidney of rats.After long-term co-administration,there were no differences in lactic acid (LCA),uric acid (URIC) and creatinine (CREA) levels between two groups.These results indicated that carvedilol increased hepatic and renal distribution of metformin,resulting in local drug interaction.