冰片促进葛根素和梓醇口服吸收入脑的研究

Borneol promotes oral absorption and penetration into brain of puerarin and catalpol

从细胞水平和动物水平考察冰片对葛根素和梓醇口服吸收及穿透血脑屏障入脑的影响,筛选适合梓葛复方口服制剂的冰片浓度。采用原代大鼠脑微血管内皮细胞和星型胶质细胞共培养建立体外血脑屏障模型,利用此模型研究6.25~100mg·L^(-1)冰片对葛根素、梓醇转运的影响。小鼠分别灌胃给予0,25,50,100 mg·kg^(-1)冰片溶液后再立即灌胃给予葛根素(200mg·kg^(-1))、梓醇(45 mg·kg-1)纳米晶混悬液,比较葛根素、梓醇在血浆和脑组织中的药动学参数。脑微血管内皮细胞和星型胶质细胞共培养7 d后,屏障功能基本形成。与未加入冰片组相比,冰片质量浓度为12.5~100 mg·L^(-1)时,葛根素、梓醇跨血脑屏障模型的渗透系数显著增大(P<0.05),冰片作用于共培养模型2 h后的跨内皮细胞电阻值极显著降低(P<0.01)。小鼠灌胃50 mg·kg-1和100 mg·kg^(-1)冰片能显著促进葛根素的口服吸收,但冰片对梓醇的口服吸收无显著影响。100 mg·kg^(-1)冰片组葛根素的AUC脑/AUC血显著高于其余3组(P<0.05),梓醇则是50 mg·kg^(-1)组最高(P<0.05)。就脑组织AUC而言,葛根素以100 mg·kg^(-1)组最大,显著高于其余各组(P<0.05);梓醇以50 mg·kg^(-1)组最大,但与100 mg·kg^(-1)组无显著性差异。可见,冰片能促进葛根素、梓醇口服给药的入脑量,质量浓度以100 mg·kg^(-1)为佳。

To investigate the effect of borneol on the oral absorption and penetration into brain of puerarin and catalpol from cell lev- el and animal level, and screen the concentration of borneol that is suitable for Zige compound oral preparation. Blood-brain barrier （BBB） model was established by co-culture of primary brain microvessel endothelial cells（BMEC） and astrocytes（As） in rats, and it was used to investigate the effect of borneol（ concentration from 6. 25 to 100 mg L-1） on the transport of puerarin and catalpol. The pharmacokinetics of puerarin and catalpol in plasma and brain of rats were compared after intragastric administration of borneol solution （0, 25, 50 and 100 mg kg-1 ） immediately followed by puerarin（200 mg kg-1 ） and catalpol（45 mg kg-1 ） nanocrystal suspen- sion. Barrier function was basically formed after co-cuhuring of brain microvascular endothelial cells and astrocytes for 7 d. The perme- ability of puerarin and catalpol across blood-brain barrier was increased significantly （ P 〈 0. 05 ） and transendothelial electrical resist- ance（TEER） values at 2 h were decreased significantly（ P 〈 0. 01 ） when the concentration of borneol was between 12. 5 to 100 mg L-1 as compared with the control group. Borneol at the dose of 50 mg kg-1 and 100 mg kg-1 could significantly increase the oral ab- sorption of puerarin（ P 〈 0. 05 ）, but there was no obvious effect for catalpol. AUCbrain/AUCblood for puerarin was highest with borneol at dose of 100 mg kg-1 （P 〈0.05）, while AUCbrain/AUCblood for catalpol was highest with borneol at dose ofS0 mg kg-1 （P 〈0.05）. AUCbrai. was highest at 100 mg kg-1 for puerarin（P 〈0. 05） ; while for catapol, it was highest at 50 mg kg-1 , but it was not signifi- cantly different from 100 mg kg-1. In conclusion, borneol could increase the amount of puerarin and catalpol in brain after oral ad-ministration and the optimized dose shall be 100 mg kg-1.