药动学参数是临床合理安全用药的重要依据。有关药物外排转运蛋白调控高原人群药动学及机制的研究国内外鲜有报道。外排转运蛋白P-gp、BCRP和MRPs是调控药动学特别是生物利用度的关键因素。课题组前期证实高原缺氧降低生物利用度，同时P-gp和mRNA表达水平显著上调；文献表明肿瘤微缺氧下长链非编码RNA(lncRNA)对P-gp转录前后进行调控。因此，我们提出高原缺氧影响药动学变化与 H19对P-gp的调控相关的假设。本课题以前期高原缺氧下生理/病理及药动学参数变化为依据，利用已建成海拔4010m高原实地实验室、高原环境模拟舱和缺氧模型，研究不同缺氧条件下不同组织和细胞中P-gp和mRNA表达水平；同时阐明过表达/沉默H19对细胞中P-gp和mRNA表达水平及转录因子（HIF1a、NF-κB等）的调控机制。以期从分子水平阐明基于P-gp的高原缺氧对药动学参数的调控机制，为高原合理用药提供依据。

Pharmacokinetic parameters are the important basis for reasonable clinical medication safety. About drug efflux transporters regulate plateau population pharmacokinetic and mechanism research rarely make the news at home and abroad. Efflux transporters include P-gp, BCRP and MRPs that are the key factors of regulating the pharmacokinetic. It is especially for the bioavailability. We preliminary confirmed plateau hypoxia reduced bioavailability, and rised significantly P-gp and mRNA expression level. Literatures show that the long chain non-coding RNA (lncRNA) regulates P-gp before and after the transcription regulation under micro-environmental hypoxia in tumor. Therefore, we propose an assumption about plateau hypoxia changes affect the pharmacokinetic. It related with H19 regulation of P-gp. This topic will depend on the result of the physiological/pathology and pharmacokinetic parameters change under plateau hypoxia in the early stage as the basis. We will research the expression level of P-gp and mRNA in different tissues and cells under the different hypoxia using the established plateau field laboratory at altitude of 4010 m , plateau environment simulation cabin and hypoxia model. Meantime, we will explain the mechanism that the expressing/silence H19 regulate the expression level of P-gp and mRNA, and transcription factors (HIF1a, NF-κB, etc.). In order to clarify the molecular level based on P - gp regulatory mechanism of pharmacokinetic parameters under the plateau hypoxia. It provides a basis for the rational use of drugs to the plateau.