平原与急进高原后(4100m)氨茶碱在大鼠体内药动学比较

Comparison of pharmacokinetics of aminophylline in rats at low altitude and acutely exposed at high altitude(an altitude of 4100 m)

目的:探讨平原组(P)与急进高原组(H)大鼠体内氨茶碱的药动学特征。方法:Wistar大鼠于平原地区禁食12 h后将0.003 8 g(约含氨茶碱3.6 mg)氨茶碱片剂灌胃给药,一周清洗期后急进高原,灌胃给药。平原组及急进高原组于给药前(0h)及给药后0.33,0.66,1,1.5,2,3,4,6,8,12,24 h由眼眶后静脉丛取血,采用液相-串联质谱方法测定血药浓度。结果:急进高原后,氨茶碱血浆超滤液浓度显著减低,因此蛋白结合率增高明显,平原组与高原组分别为37.05%和74.17%。氨茶碱急进高原组与平原组相比药动学参数发生显著变化,房室模型参数Ka显著增大,与高原组相比半衰期从(2.365±0.448)h增大到(2.944±0.694)h,体内平均驻留时间延长,峰浓度增大,达峰时间缩短,总清除率降低。结论:急进高原后,氨茶碱在大鼠体内代谢过程发生显著变化,研究结果为平原和急进高原后临床合理应用氨茶碱提供参考依据。

OBJECTIVE To investigate the pharmacokinetics of aminophylline in rats living at low altitude（P）and after acutely exposed to high altitude（H）.METHODS Aminophylline tablet 0.0038 g was intragastrically administered to rats at low altitude（~50 m）and exposed to high altitude（~4100 m）：rats residing at low altitude,and these after exposed for 1-week washout period to high altitude.Blood samples were collected from venous plexus posterior to socket and put into heparinized centrifuge tubes 0,0.33,0.66,1,1.5,2,3,4,6,8,12 and24 hours after drug administration.Plasma concentration of aminophylline was determined by LC-MS/MS.RESULTS Concentration of aminophylline in plasma ultrafiltrate decreased significantly after exposure to high altitude,therefore,the protein binding was significantly higher after acutely exposed to high altitude（74.17%）compared with those at low altitude（37.05%）.Aminophylline pharmacokinetic parameters at low altitude were significantly different from those of rats acutely exposed to high altitude.The Ka of compartmental model was significantly higher in rats exposed to high altitude compared with those at low altitude.Comparison of the t1/2 obtained in plasma in the2 groups of this study showed an increase from2.365±0.448 to 2.944±0.694 hours in rats acutely exposed to high altitude.The MRT was prolonged and the Clz/F was lower in rats exposed to high altitude.The Cmax was significantly higher in rats acutely exposed to high altitude than those at low altitude.We also observed shortened Tmax and decreased total clearance rate.CONCLUSION This study shows significant changes in disposition of aminophylline in rats acutely exposed to high altitude,which will provide reference for clinical rational application of aminophylline at low altitude and after acute exposure to high altitude.