MODULATION OF NOSE-TO-BRAIN DELIVERY OF A P-GP (MDR1) SUBSTRATE MODEL DRUG IN ANESTHETIZED RATS
Franciska Erdő1, Luca Bors1, Ágnes Bajza1, Benedek József Tasi1, György Cserey1, Míra Mándoki2, Tímea Imre3, Pál Szabó3
1 Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, H-1083Budapest, Práter u. 50a.; 2Department of Pathology, University of Veterinary Medicine Budapest H-1078Budapest, István utca 2.;3Research Centre for Natural Sciences, MS Metabolomics Research Group, H-1117, Budapest, Magyar tudósok krt 2.
The main challenge in the delivery of CNS acting drugs is to overcome the blood-brain barrier (BBB). There are different strategies to enhance the drug concentrations in the brain, and intranasal administration is one of the promising options to bypass the BBB. The expression of efflux transporters in the nasal cavity was described recently by different workgroups. These proteins have a restrictive effect on the epithelial diffusion of substrate drugs. The aim of the present study was to investigate whether the topical or systemic modulation of P-glycoprotein (P-gp) has an influence on the nasal absorption of P-gp substrate model drug (quinidine). On the other hand the effect of adrenalin as a topical vasoconstrictor has also been tested. Quinidine was applied intranasally (IN) and the modulator (PSC-833) IN or IV. The IN modulator failed to increase the brain levels of quinidine, while IV PSC-833 dramatically increased the brain levels and in parallel reduced the blood concentrations. High dose adrenaline also enhanced the brain exposure to quinide, but the blood levels at the same time remained unchanged. Our results indicate that P-gp proteins, limiting quinidine absorption, are mainly localized in the apical membrane of capillary endothelial cells in the microvasculature of olfactory epithelium. The externally administered inhibitor has no effect on the drug absorption to the brain. These findings call attention to a possible combination therapy against brain tumors or neurodegenerative disorders, where the therapeutic drug can be applied nasally and the delivery enhancer is administered systemically. References: Erdő F et al. Brain Res Bull. 2018;143:155-170. Hada N et al, Eur J Pharm Sci. 2017, 1;102:46-54. Al-Ghabeish M et al, Mol Pharm. 2015 Aug 3;12(8):2742-54. Shingaki T et al, Drug Metab Pharmacokinet. 2011,26(3):248-55. Bors LA & Erdő F, Sci. Pharm. 2019, 87(1), 6, 1-28.