摘要
目的探究模拟失重环境对SD大鼠体内异丙嗪(PMZ)药代动力学的影响,为航天环境下的安全用药提供科学依据。方法选取30只SPF级雄性SD大鼠,按照随机数字表法将其分为常重组(6只)和模拟失重组(24只)。模拟失重组采用Morey-Holton模型模拟大鼠失重状态并按照尾部悬吊时间分为模拟失重1、2、3、4周组,每组6只。造模完成后,常重组和模拟失重组SD大鼠灌胃PMZ 2.625 mg/kg,于给药后0.083、0.250、0.500、1.000、2.000、4.000、6.000、12.000、24.000、48.000 h眼眶后静脉丛取血,建立LC-MS/MS方法并测定血浆中PMZ及其代谢产物异丙嗪亚砜(PMZSO)浓度,同时计算药代动力学参数。结果与常重组比较,模拟失重2、3、4周组PMZ的AUC_((0~∞))降低(P<0.05);模拟失重1、2、3周组t_(1/2z)升高(P<0.05);模拟失重2、4周组MRT_((0~∞))缩短(P<0.05);模拟失重3周组CLz/F升高(P<0.05);模拟失重1、3周组Vz/F升高(P<0.05)。与常重组比较,模拟失重3、4周组PMZSO的C_(max)升高(P<0.05),模拟失重1、2、3周组AUC_((0~∞))降低(P<0.05),模拟失重3周组T_(max)升高(P<0.05),模拟失重4周组t_(1/2z)缩短、MRT_((0~∞))降低(P<0.05),模拟失重2周组CLz/F升高(P<0.05),模拟失重1、2、3、4周组Vz/F升高(P<0.05)。结论模拟失重条件下,PMZ吸收减少,体内清除速率减缓,代谢产物PMZSO排泄加快,体内分布范围扩大。后续需要建立生理药代动力学模型预测航天失重环境下用药,为航天环境下PMZ的安全用药提供科学依据。
Objective To investigate the effect of simulated microgravity environment on pharmacokinetics of Promethazine(PMZ)in SD rats,and to provide a scientific basis for safe drug use in the aerospace environment.Methods Thirty SPF-grade male SD rats were selected,and they were divided into control group(6 rats)and simulated microgravity group(24 rats).The Morey-Holton model was used to simulate microgravity state of rats and they were divided into simulated microgravity 1,2,3 weeks and 4 weeks groups according to tail suspension time,with 6 rats in each group.After the modeling was completed,normal gravity group and simulated microgravity group SD rats were gavaged with PMZ at 2.625 mg/kg,blood was collected from the posterior orbital venous plexus at 0.083,0.250,0.500,1.000,2.000,4.000,6.000,12.000,24.000 hours,and 48.000 hours after administration.LC-MS/MS method was established and the concentrations of PMZ and its metabolite promethazine sulfoxide(PMZSO)in plasma were determined.Meanwhile,the pharmacokinetic parameters were calculated.Results Compared with normal gravity group,the AUC_((0~∞))of PMZ in simulated microgravity 2,3 weeks,and 4 weeks groups decreased(P<0.05);t_(1/2z) in simulated microgravity 1,2 weeks,and 3 weeks groups increased(P<0.05),MRT_((0~∞))in simulated microgravity 2,4 weeks groups shortened(P<0.05);CLz/F in simulated microgravity 3 weeks group increased(P<0.05);Vz/F in simulated microgravity 1,3 weeks groups increased(P<0.05).Compared with normal gravity group,C_(max) of PMZSO in simulated microgravity 3,4 weeks groups increased(P<0.05);AUC_((0~∞))in simulated microgravity 1,2 weeks,and 3 weeks groups decreased(P<0.05);and T_(max) in simulated microgravity 3 weeks group increased(P<0.05);t_(1/2z) shortened and MRT_((0~∞))decreased in simulated microgravity 4 weeks groups(P<0.05),CLz/F increased in simulated microgravity 2 weeks group(P<0.05);Vz/F in simulated microgravity 1,2,3weeks,and 4 weeks groups increased(P<0.05).Conclusion Under simulated microgravity conditions,the absorption of PMZ decreases,the clearance rate in the body slows down,the excretion of metabolite PMZSO accelerates,and the distribution range in the body expands.Subsequently,a physiological pharmacokinetic model needs to be established to predict drug use in microgravity environment of aerospace,providing a scientific basis for the safe drug use of PMZ in the aerospace environment.
作者
张旸
李勃睿
关丽
马丽莎
林佳艳
刁春妍
王庆伟
刘雪英
ZHANG Yang;LI Borui;GUAN Li;MA Lisha;LIN Jiayan;DIAO Chunyan;WANG Qingwei;LIU Xueying(Teaching and Research Section of Medicinal Chemistry and Medicinal Analysis,Department of Pharmacy,Air Force Medical University,Shaanxi Province,Xi’an 710032,China;School of Clinical Medicine,Xizang Minzu University,Shaanxi Province,Xianyang 712082,China;Department of Pharmacy,Xi’an Qinhuang Hospital,Shaanxi Province,Lintong 710006,China)
出处
《中国医药导报》
2025年第16期1-6,共6页
China Medical Herald
基金
军队后勤科研项目“太空环境对药物影响及军事应用研究”子课题(BWS17J028)。
关键词
异丙嗪
航天运动病
模拟失重
药代动力学
Promethazine
Space motion sickness
Simulated microgravity
Pharmacokinetics
作者简介
张旸(1989.4-),男,博士,研究方向:药物分析学与药代动力学;通讯作者:刘雪英(1969.3-),女,博士,副教授,主要从事药代动力学及药物合成与活性研究。
