【摘要】 目的观测高原缺氧对氯沙坦钾代谢动力学的影响。方法将雄性SD大鼠随机分为常氧组（P）、急性缺氧组（AH）、慢性缺氧组（CH）和慢性缺氧返回常氧组（CH-P）。各组大鼠均经腹主静脉取血测定其血常规及生化指标;用HE染色法观察心、肺、肝、肾组织形态学变化。单次灌胃给药后,在0.083、0.250、0.500和1、2、3、4、6、8、12、24 h时间点从大鼠眼眶后静脉丛取血,采用UPLC-MS法测定血浆中氯沙坦钾及其主要代谢产物氯沙坦羧酸血药浓度并计算其药物代谢动力学参数。结果与常氧组相比,各缺氧组血常规及生化指标均发生显著变化,主要表现为HGB、ALB、GLU、LDL升高,HCT、MCV、MPV、ALT、AST、TP、GLO、TC降低;缺氧组心肌组织、肾脏组织、肺脏组织、肝脏组织除局部微小损伤及偶见炎性细胞点状浸润外,均未见明显实质损伤。高原缺氧环境下,氯沙坦钾及氯沙坦羧酸的药物代谢动力学特征发生显著改变,相较于常氧组里的两个缺氧组主要表现为AUC、C_max降低,t_1/2缩短,CL、V_d升高;慢性缺氧返回常氧组的AUC、C_max升高,t_1/2延长,CL、V_d降低。结论高原缺氧对氯沙坦钾代谢动力学存在影响:口服吸收减慢,程度降低,消除加快。更多还原

【Abstract】 Objective To investigate the effects of high altitude hypoxia on the pharmacokinetics of losartan potassium.Methods Male SD rats were randomly divided into normoxia group（P）,acute hypoxia group（AH）,chronic hypoxia group（CH）and chronic hypoxia return to normoxia group（CH-P）.The rats in each group were taken blood from the abdominal aorta to determine their blood routine and biochemical indexes; HE staining method was used to observe the morphological changes of heart, lung, liver and kidney tissues.Blood was taken from the rat’s retro-orbital venous plexus at 0.083,0.250,0.500,1,2,3,4,6,8,12,and 24 h after a single intragastric administration.UPLC-MS was used to determine the plasma concentration of losartan potassium and its main metabolite EXP 3174,and their pharmacokinetic parameters were calculated.Results Compared with Group P,the blood routine and biochemical indexes of the rats in the hypoxia group changed significantly, mainly manifested as the increasing of HGB,ALB,GLU,LDL and the decreasing of HCT,MCV,MPV,ALT,AST,TP,GLO and TC; the heart, lung, liver and kidney tissues of the hypoxia group had no obvious physical damage except for minor damage and occasional punctate infiltration of inflammatory cells.The pharmacokinetic characteristics of losartan potassium and EXP 3174 changed significantly at hypoxia.Compared with Group P,the AUC and C_max of two hypoxia groups were decreased, t_1/2 was shortened, CL and V_d were increased; while the AUC and C_max of Group CH-P were increased, t_1/2 were prolonged, CL and V_d were decreased.Conclusion High altitude hypoxia has an impact on the pharmacokinetics of losartan potassium, including slowing down oral absorption, reducing the degree and accelerating the elimination.更多还原