酒石酸卡巴拉汀鼻腔吸收及脑靶向性评价

Intranasal absorption of rivastigmine hydrogen tartrate and brain targeting evaluation

本文研究了影响酒石酸卡巴拉汀鼻腔吸收的因素,考察了其体内药代动力学行为并评价了其脑靶向性。采用大鼠在体鼻腔循环法研究酒石酸卡巴拉汀浓度和药液p H值对药物鼻腔吸收的影响;大鼠静脉注射及鼻腔给药后,采用高效液相色谱(high performance liquid chromatography,HPLC)法测定血浆及脑组织中药物浓度,并计算药动学参数、脑靶向指数(drug targeting index,DTI)和药物鼻脑直接转运百分比(nose-to-brain direct transport percentage,DTP)。研究表明,酒石酸卡巴拉汀在鼻腔内的吸收机制为被动扩散,p H 6.0时药物吸收速率常数最大。该药物鼻腔给药的绝对生物利用度为73.58%。与静脉注射相比,鼻腔给药后药物入脑更加迅速,在脑组织的分布显著增加,DTI为静脉注射的195.27%。鼻腔给药后约48.79%药物可从鼻腔通道直接转运至脑部而未经全身血液循环,显著提高了药物的入脑速度和程度。同时,与静脉注射相比,酒石酸卡巴拉汀在脑部的清除半衰期延长了1.4倍。综上,酒石酸卡巴拉汀鼻腔给药不仅可有效促进药物的吸收,而且能显著加快药物的入脑速度和增强药物的脑组织分布,更有利于中枢神经系统疾病的治疗。

To investigate factors influencing the intranasal absorption of rivastigmine hydrogen tartrate （RHT）, we studied the pharmacokinetics of RHT after intranasal administration and evaluated its brain targeting behavior. In situ rat nasal perfusion model was used in the study and pH impact was examined on the intranasal absorption of RHT. High performance liquid chromatography （HPLC） method was established to measure RHT concentration in the plasma and brain tissue after intranasal and intravenous administration. The pharmacokinetic parameters, drug targeting index （DTI）, and nose-to-brain direct transport percentage （DTP） were calculated. It was demonstrated that the intranasal absorption mechanism of RHT was passive diffusion. The absorption rate was highest at pH 6.0. The absolute bioavailability of intranasally administrated RHT was 73.58%. Compared with that of intravenous administration, RHT absorption into the brain was faster and more efficient after intranasal delivery, and the DTI value was 195.27% of intravenous injection. Moreover, 48.79% of the drug can be absorbed directly from the nose into the brain without systematic circulation. Meanwhile, drug elimination half-time in the brain was prolonged by 1.4 fold compared to that of intravenous injection. In conclusion, intranasal administration of RHT not only improves drug absorption into the system, but also enhances drug absorption rate and content in the brain remarkably, which is an advantage in the treatment of central nervous system-related diseases.