磷酸川芎嗪鼻用pH敏感型原位凝胶大鼠血液和脑部药动学研究

Pharmacokinetics of Nasal Tetramethylpyrazine Phosphate pH-sensitive in Situ Gel in Rat Blood and Brain

目的研究磷酸川芎嗪(TMPP)鼻用pH敏感型原位凝胶(TMPP凝胶)大鼠血液和脑部药动学。方法大鼠鼻腔给予TMPP凝胶和TMPP溶液后,利用血液微透析与脑部微透析技术同步进行血液药动学与脑部药动学研究,高效液相色谱法测定并计算透析液中TMPP的浓度,用Kinetica 4.4软件计算药动学参数。结果两种鼻腔给药制剂在大鼠血液和脑部的药-时曲线均符合二室开放模型,TMPP溶液组和凝胶组血液中的主要药动学参数:tmax分别为(15.0±1.0),(35.0±1.0)min;ρmax分别为(5.857±1.3),(5.848±1.0)μg.mL-1;AUC0～∞分别为(529.9±68.6),(642.7±54.3)μg.min.mL-1。脑部的主要药动学参数:tmax分别为(15.0±1.0),(35.0±1.0)min;ρmax分别为(7.134±0.8),(6.738±1.1)μg.mL-1;AUC0～∞分别为(615.4±71.2),(801.4±67.5)μg.min.mL-1。结论 TMPP凝胶易于通过鼻腔吸收进入脑部,并能起到缓释效应。

OBJECTIVE To study the pharmacokinetics of nasal tetramethylpyrazine phosphate （TMPP） pH-sensitive in situ gel in rat blood and brain. METHODS After intranasal administration of TMPP pH-sensitive in situ gel and TMPP solution respectively in rats, microdialysis was used to collect brain and blood samples simultaneously. The concentration of TMPP in the sample was measured by HPLC. Main pharmacokinetic parameters were calculated by Kinetica 4.4 pharmacokinetic software. RESULTS The concen- tration-time curves of the two preparations fitted to two-compartment model. The main pharmacokinetic parameters of TMPP pH-sensi- rive in situ gel and TMPP solution in blood and in brain were as follows： in blood： tmax （ 15. 0 ±1. 0） and （35.0 ± 1.0） min; Pmax （5. 857 ± 1.3） and （ 5. 848 ± 1.0 ） μg · mL^- 1 ; AUC0-∞ （ 529. 9 ±68.6 ） and （ 642. 7 ± 54. 3 ） μg · mL · min^- 1, respectively. In brain： tmax（15.0±1.0） and （35.0±1.0） min; ρmax（7.134±0.8）and（6.738±1.1）μg · mL^-1;AUC0-∞ （615.4±71.2） and （801.4 ± 67. 5 ） μg · mL ·min^ - 1, respectively. CONCLUSION TMPP in the pH-sensitive in situ gel can be easily absorbed and transferred into brain after intranasal administration, and the gel shows sustained-release effect.