高原急性缺氧对大鼠药物转运体PEPT1及阿莫西林药代动力学的影响

Effect of amoxicillin on the expression of PEPT1 and pharmacokinetics upon acute hypoxia at high altitude in rat

寡肽转运体1(PEPT1)与药物疗效、疾病的关联性越来越受到重视,成为提高药物生物利用度很有前途的一种策略,也是临床合理化给药的重要出发点。本研究考察了急进高原缺氧对大鼠PEPT1的表达及其底物药物阿莫西林药代动力学的影响。结果显示,在小肠、肾脏,高原组中PEPT1的mRNA、蛋白表达显著上升36.87%、216.21%、577.8%、535.9%;在肝脏,PEPT1的mRNA表达和蛋白却下降43.90%和84.7%。与平原组相比,高原组阿莫西林的AUC、t_(max)、C_(max)、MRT、t_(1/2)显著性增加312.17%、63.04%、110.93%、67.11%、16.96%,V_d明显降低74.51%。急进高原缺氧后,大鼠药物转运体PEPT1表达会发生明显的变化,从而影响底物阿莫西林的药代动力学。

The relationship between PEPT1（peptide transporter）and drug efficacy has drawn more and more attention in the treatment of disease.PEPT1 represents a promising strategy for improvement of drug bioavailability and an important starting point for clinical rationalization of drug selection.The effect of PEPT1 on transport and pharmacokinetics of amoxicillin was investigated under hypoxia condition at high altitude in rat.The mRNA and protein expressions of PEPT1 were increased by 36.87%,216.21%,577.8% and 535.9% respectively in the hypoxia group in the small intestine and kidney of rats.However,the mRNA and protein expressions of PEPT1 were reduced by 43.90% and 84.7% in the liver.Compared with the control group,the AUC,t_（max）,C_（max）,MRT and t_（1/2） of amoxicillin were significantly enhanced by 312.17%,63.04%,110.93%,67.11% and 16.96% respectively in the hypoxia group,while the CL was significantly decreased by 74.51%.After acute exposure to high altitude,the expressions of drug transporter PEPT1 were distinctly changed in rat tissues,which can affect the pharmacokinetics of amoxicillin.