Stevens Jasper, Suidgeest Ernst, van der Graaf Piet Hein, Danhof Meindert, de Lange Elizabeth C M
Division of Pharmacology, LACDR Leiden University, Leiden, The Netherlands.
Pharm Res. 2009 Aug;26(8):1911-7. doi: 10.1007/s11095-009-9907-1. Epub 2009 May 19.
To develop a new minimal-stress model for intranasal administration in freely moving rats and to evaluate in this model the brain distribution of acetaminophen following intranasal versus intravenous administration.
Male Wistar rats received one intranasal cannula, an intra-cerebral microdialysis probe, and two blood cannulas for drug administration and serial blood sampling respectively. To evaluate this novel model, the following experiments were conducted. 1) Evans Blue was administered to verify the selectivity of intranasal exposure. 2) During a 1 min infusion 10, 20, or 40 microl saline was administered intranasally or 250 microl intravenously. Corticosterone plasma concentrations over time were compared as biomarkers for stress. 3) 200 microg of the model drug acetaminophen was given in identical setup and plasma, and brain pharmacokinetics were determined.
In 96% of the rats, only the targeted nasal cavity was deeply colored. Corticosterone plasma concentrations were not influenced, neither by route nor volume of administration. Pharmacokinetics of acetaminophen were identical after intravenous and intranasal administration, although the Cmax in microdialysates was reached a little earlier following intravenous administration.
A new minimal-stress model for intranasal administration in freely moving rats has been successfully developed and allows direct comparison with intravenous administration.
建立一种用于自由活动大鼠鼻腔给药的新的低应激模型，并在此模型中评估对乙酰氨基酚经鼻腔给药与静脉给药后的脑内分布情况。
雄性Wistar大鼠分别植入一根鼻腔插管、一个脑内微透析探针以及两根血管插管，用于给药和连续采血。为评估这一新模型，进行了以下实验。1）给予伊文思蓝以验证鼻腔暴露的选择性。2）在1分钟输注期间，经鼻腔给予10、20或40微升生理盐水，或经静脉给予250微升生理盐水。比较不同时间点的皮质酮血浆浓度，将其作为应激的生物标志物。3）在相同设置下给予200微克模型药物对乙酰氨基酚，测定血浆和脑内的药代动力学。
在96%的大鼠中，仅目标鼻腔被染成深色。皮质酮血浆浓度不受给药途径和给药体积的影响。对乙酰氨基酚经静脉和鼻腔给药后的药代动力学相同，尽管静脉给药后微透析液中的Cmax出现得稍早一些。
已成功建立一种用于自由活动大鼠鼻腔给药的新的低应激模型，该模型可与静脉给药进行直接比较。
