Affiliation:
1. Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
Abstract
Blood-to-retina transport across the inner blood–retinal barrier (BRB) is a key determinant of retinal drug concentration and pharmacological effect. Recently, we reported on the amantadine-sensitive drug transport system, which is different from well-characterized transporters, at the inner BRB. Since amantadine and its derivatives exhibit neuroprotective effects, it is expected that a detailed understanding of this transport system would lead to the efficient retinal delivery of these potential neuroprotective agents for the treatment of retinal diseases. The objective of this study was to characterize the structural features of compounds for the amantadine-sensitive transport system. Inhibition analysis conducted on a rat inner BRB model cell line indicated that the transport system strongly interacts with lipophilic amines, especially primary amines. In addition, lipophilic primary amines that have polar groups, such as hydroxy and carboxy groups, did not inhibit the amantadine transport system. Furthermore, certain types of primary amines with an adamantane skeleton or linear alkyl chain exhibited a competitive inhibition of amantadine uptake, suggesting that these compounds are potential substrates for the amantadine-sensitive drug transport system at the inner BRB. These results are helpful for producing the appropriate drug design to improve the blood-to-retina delivery of neuroprotective drugs.
Funder
Japan Society for Promotion of Science
Japan Science and Technology Agency
Subject
Drug Discovery,Pharmaceutical Science,Molecular Medicine
Reference34 articles.
1. The inner blood-retinal barrier: Cellular basis and development;Ramos;Vis. Res.,2017
2. The blood-retina barrier in health and disease;Campbell;FEBS J.,2023
3. Recent advances in drug and nutrient transport across the blood-retinal barrier;Kubo;Expert Opin. Drug Metab. Toxicol.,2018
4. Propranolol transport across the inner blood-retinal barrier: Potential involvement of a novel organic cation transporter;Kubo;J. Pharm. Sci.,2013
5. Shinozaki, Y., Akanuma, S., Mori, Y., Kubo, Y., and Hosoya, K. (2021). Comprehensive evidence of carrier-Mediated distribution of amantadine to the retina across the blood-retinal barrier in rats. Pharmaceutics, 13.