Comparison of Brain Regional Distribution Kinetics of DB213 after Intranasal and Intravenous Administrations
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摘要Purpose
Intranasal administration (IN) has gained more and more attention over the recent years for its unique potential to bypass the blood-brain barrier (BBB). However, there are only limited studies on the understanding of brain distribution kinetics of IN administered therapeutics. An HIV-1 replication inhibitor DB213 targeting HIV-associated neurocognitive disorders was chosen as the model drug. This study aims to 1) investigate the brain distribution kinetics of IN administered DB213 and 2) illustrate the difference between the brain distribution pathway of DB213 via IN and the traditional intravenous route (IV).
Methods
Sprague-Dawley rats were administered with DB213 water solution via IV or IN at a dose of 10 mg/kg. At each of the different time points post dosing (15, 30, 60, 90 and 120 min), a batch of SD rats (n=5 per time point per route) were sacrificed followed by collection of plasma, cerebrospinal fluid (CSF) and the whole brain samples. With the help of a brain matrix, the whole brain was immediately dissected into nine different regions: olfactory bulb, trigeminal nerve, frontal cortex, medium cortex, posterior cortex, hippocampus, striatum, cerebellum and tissues containing mid brain, thalamus and hypothalamus. All plasma, CSF and brain samples were then analyzed by an established LC/MS/MS method.
Results
After IV administration, trigeminal nerve had the highest DB213 concentration at each time point (p<0.05), whereas the other eight brain regions didn’t show significant difference in DB213 concentration (p>0.05). With the increase of time, DB213 concentration in trigeminal nerve showed the trend to decrease with other regions peaked at 60 min, which was parallel with the change of CSF over time.
After IN administration, the concentration of DB213 in nine different regions had a significant difference between each other (p<0.05). At each time point, the olfactory bulb demonstrated the highest DB213 concentration, followed by the trigeminal nerve. The concentration of DB213 in both olfactory bulb and trigeminal nerve decreased with the increase of time, which indicated both olfactory bulb and trigeminal nerve were the entry point for DB213 to the CNS system after its nasal administration. In other regions of brain, the concentration changed differently from 0 to 120 min. Under the assumption that DB213 was distributed only by passive diffusion, the distribution pathways of DB213 via IN delivery were identified and shown in Figure 1. Unlike observations from IV administration, the CSF drug concentration after IN administration showed a trend of increase from 0 to 120 min, which was not parallel with the brain regional drug concentration change.
Compared with the traditional IV route, at each time point, IN delivered DB213 had higher concentration at each of the brain regions, which indicated IN route had the potential of direct nose-to-brain transportation of DB213. Moreover, the different trend of regional drug concentration between IV and IN suggested there could exist pathways other than passing through the BBB that were responsible for the brain distribution of DB213 via IN administration.
Conclusion
The brain distribution pathways of bot IV and IN delivered DB213 were identified. Compared with traditional IV route, olfactory bulb and trigeminal nerve served as entry points for the intranasal delivered DB213.

This work was generously supported by the Lui Che Woo Institute of Innovative Medicine BRAIN Initiative, Faculty of Medicine, The Chinese University of Hong Kong (Project Number 8303404).
出版社接受日期23.07.2017
著者Qianwen Wang, Shaohong Peng, Qian Zhang, Chun-Ho Wong, H.Y. Edwin Chan, Zhong Zuo
會議名稱AAPS Annual Meeting and Exposition 2016
會議開始日13.11.2016
會議完結日17.11.2016
會議地點Denver
會議國家/地區美國
出版年份2016
月份11
語言美式英語

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