Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal.
Int J Pharm. 2015 Jul 25;490(1-2):39-46. doi: 10.1016/j.ijpharm.2015.05.021. Epub 2015 May 12.
Pharmacoresistance is considered one of the major causes underlying the failure of the anticonvulsant therapy, demanding the development of alternative and more effective therapeutic approaches. Due to the particular anatomical features of the nasal cavity, intranasal administration has been explored as a means of preferential drug delivery to the brain. The purpose of the present study was to assess the pharmacokinetics of lamotrigine administered by the intranasal route to mice, and to investigate whether a direct transport of the drug from nose to brain could be involved. The high bioavailability achieved for intranasally administered lamotrigine (116.5%) underscored the fact that a substantial fraction of the drug has been absorbed to the systemic circulation. Nonetheless, the heterogeneous biodistribution of lamotrigine in different brain regions, with higher concentration levels attained in the olfactory bulb comparatively to the frontal cortex and the remaining portion of the brain, strongly suggest that lamotrigine was directly transferred to the brain via the olfactory neuronal pathway, circumventing the blood-brain barrier. Therefore, it seems that intranasal route can be assumed as a suitable and valuable drug delivery strategy for the chronic treatment of epilepsy, also providing a promising alternative approach for a prospective management of pharmacoresistance.
药物抗药性被认为是导致抗癫痫药物治疗失败的主要原因之一，这就需要开发替代的、更有效的治疗方法。由于鼻腔具有特殊的解剖结构，人们已经探索了经鼻给药作为将药物优先递送到大脑的一种手段。本研究旨在评估拉莫三嗪经鼻腔给药给小鼠的药代动力学，并研究药物是否可能直接从鼻子运输到大脑。鼻腔给予的拉莫三嗪（116.5%）具有很高的生物利用度，这表明药物的很大一部分已被吸收到全身循环中。尽管如此，拉莫三嗪在不同脑区的不均匀分布，在嗅球中达到的浓度水平明显高于额叶皮质和大脑的其余部分，这强烈表明拉莫三嗪是通过嗅神经元途径直接转移到大脑的，绕过了血脑屏障。因此，鼻腔给药途径似乎可以作为治疗癫痫的一种合适且有价值的药物递送策略，也为药物抗药性的前瞻性管理提供了一种有前途的替代方法。
