甲磺酸雷沙吉兰鼻用凝胶剂在大鼠体内的药动学及鼻黏膜纤毛毒性研究  

Studies on pharmacokinetics of rasagiline mesylate nasal gel in rats and its nasal mucociliary toxicity

作　　者：谷福根[1] 张艺馨 吴春芝[1] GU Fu-gen;ZHANG Yi-xin;WU Chun-zhi(Affiliated Hospital, Inner Mongolia Medical University, Hohhot 010050, China;School of Pharmacy, Inner Mongolia Medical University, Hohhot 010110, China)

机构地区：[1]内蒙古医科大学附属医院,呼和浩特010050 [2]内蒙古医科大学药学院,呼和浩特010110

出　　处：《中国新药杂志》2018年第13期1555-1559,共5页Chinese Journal of New Drugs

摘　　要：目的:研究甲磺酸雷沙吉兰(rasagiline mesylate,RM)鼻用凝胶剂在大鼠体内的药动学及鼻黏膜纤毛毒性。方法:以灌胃(ig)250 mg·kg-1RM的溶液为对照组,大鼠鼻腔给予20 mg·kg-1RM鼻用凝胶剂后,采用HPLC法测定血浆中RM浓度并计算其主要药动学参数。以离体蟾蜍上颚黏膜为模型,观察RM鼻用凝胶剂处理后,上颚黏膜的形态变化并记录纤毛持续摆动时间(LTCM)。结果:RM在大鼠体内的药动学过程符合二室模型。RM鼻用凝胶剂鼻腔给药与RM溶液ig给药后,测得二者的主要药动学参数Tmax分别为(3.29±0.76)和(9.29±3.45)min,Cmax分别为(18.70±10.11)和(9.35±4.71)μg·m L-1,AUC0~∞分别为(7.44±1.02)和(10.33±2.23)μg·h·m L-1,RM鼻用凝胶剂的相对生物利用度(Fr)高达974.3%。RM鼻用凝胶剂处理后,首次测得蟾蜍上颚黏膜的LTCM为(60.8±4.3)min,纤毛摆动恢复后,再次测得的LTCM为(194.8±6.6)min,样本总的LTCM为生理盐水的84%。结论:RM鼻用凝胶剂体内吸收迅速,生物利用度高、鼻黏膜纤毛毒性小,是一种具有开发前景的新制剂。Objective： To study the pharmacokinetics of rasagiline mesylate（ RM） nasal gel in rats and further investigate the nasal mucociliary toxicity of the new preparation. Methods： 250 mg·kg-1 of RM solution（ i. g） was used as control,the RM plasma concentrations after nasal administration（ i. n.） of 20 mg·kg-1 of the drug nasal gel to rats were determined using HPLC method and afterwards the main pharmacokinetic parameters of the drug were also estimated. Meantime,the morphological changes and the lasting time of ciliary movement（ LTCM） of isolated upper palate mucosa of toad were observed after they were treated with RM nasal gel. Results：The pharmacokinetics profiles of RM administered either nasally or orally to rats both conformed to an open twocompartment model. The main pharmacokinetics parameters of the drug nasal gel and its oral solution such as Tmax,Cmaxand AUC0-∞were（ 3. 29 ± 0. 76） min and（ 9. 29 ± 3. 45） min,（ 18. 70 ± 10. 11） and（ 9. 35 ± 4. 71） μg·m L-1,and（ 7. 44 ± 1. 02） and（ 10. 33 ± 2. 23） μg·h·m L-1,respectively. The relative bioavailability（ Fr） of RM nasal gel was up to 974. 3%. The first-time recorded LTCM of the upper mucosa of toads treated with RM nasal gel was（ 60. 8 ± 4. 3） min. After cilia movement restored,the second-time obtained LTCM was（ 194. 8 ± 6. 6） min. Thetotal LTCM for the samples was 84% of 0. 9% normal saline. Conclusion： The RM nasal gel will be a promising dosage form with rapid absorption,high bioavailability and lower nasal mucosa toxicity.

关 键 词：甲磺酸雷沙吉兰 鼻用凝胶剂 药动学 黏膜纤毛毒性 

分 类 号：R969[医药卫生—药理学] R992[医药卫生—药学]