背景:高原环境影响药物的药代动力学(PK)参数,PK参数是指导临床合理用药的重要理论依据。华法林是临床常用的香豆素类口服抗凝剂,但它有一个狭窄的治疗窗口和广泛的个体差异。然而,高原环境对华法林PK和药效学(PD)的影响尚不清楚。
目的:本研究的目的是研究高原环境对大鼠华法林PK和PD的影响。
方法:大鼠随机分为平原组和高原组,给予2mg/kg华法林后通过眼眶静脉丛采集血液。通过液相色谱-串联质谱法(LC-MS/MS)测定血浆样品中的华法林浓度,并使用WinNonlin8.1软件通过非区室模型计算PK参数。同时,PXR的表达,还通过蛋白质印迹法测定肝组织中的P-gp和CYP2C9。通过测量活化部分凝血活酶时间(APTT)和凝血酶原时间(PT)值,然后根据PT计算国际标准化比率(INR)值,探讨了高原环境对华法林PD的影响。
结果:观察到高原大鼠华法林的PK行为和PD的显着变化。与普通老鼠相比,峰值浓度(Cmax)和血浆浓度-时间曲线下面积(AUC)显着增加了50.9%和107.46%,分别。同时,高海拔环境显著抑制PXR的表达,肝组织中的P-gp和CYP2C9。PD研究结果表明,高海拔环境显着延长PT,APTT和INR值。
结论:高原环境抑制华法林的代谢,增加华法林的吸收,增强抗凝作用。建议应重新评估高海拔地区患者华法林的最佳剂量。
BACKGROUND: High altitude environment affects the pharmacokinetic (PK) parameters of drugs and the PK parameters are an important theoretical basis for guiding the rational clinical use of drugs. Warfarin is an oral anticoagulant of the coumarin class commonly used in clinical practice, but it has a narrow therapeutic window and wide individual variation. However, the effect of high altitude environment on PK and pharmacodynamic (PD) of warfarin is unclear.
OBJECTIVE: The objective of this study is to investigate the effect of a high altitude environment on PK and PD of warfarin in rats.
METHODS: Rats were randomly divided into plain group and high altitude group and blood samples were collected through the orbital venous plexus after administration of 2 mg/kg warfarin. Warfarin concentrations in plasma samples were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and PK parameters were calculated by the non-compartment model using WinNonlin 8.1 software. Meanwhile, the expression of PXR, P-gp and CYP2C9 in liver tissues was also determined by western blotting. The effect of high altitude environment on PD of warfarin was explored by measuring activated partial thromboplastin time (APTT) and prothrombin time (PT) values and then calculated international normalized ratio (INR) values based on PT.
RESULTS: Significant changes in PK behaviors and PD of warfarin in high altitude-rats were observed. Compared with the plain-rats, the peak concentration (Cmax) and the area under the plasma concentration-time curve (AUC) increased significantly by 50.9% and 107.46%, respectively. At the same time, high altitude environment significantly inhibited the expression of PXR, P-gp and CYP2C9 in liver tissues. The results of the PD study showed that high altitude environments significantly prolonged PT, APTT and INR values.
CONCLUSIONS: High altitude environment inhibited the metabolism and increased the absorption of warfarin in rats and increased the effect of anticoagulant effect, suggesting that the optimal dose of warfarin for patients at high altitude should be reassessed.