Brain Targeting of Acyl-CoA:Cholesterol O-Acyltransferase-1 Inhibitor K-604 via the Intranasal Route Using a Hydroxycarboxylic Acid Solution

Autor:	Noriko Noguchi, Yasuomi Urano, Masayoshi Miyamoto, Yoshihiko Tsunenari, Shin-ichiro Ogawa, Kimiyuki Shibuya, Shigeru Morikawa
Jazyk:	angličtina
Rok vydání:	2019
Předmět:	Cholesterol General Chemical Engineering General Chemistry Acyl CoA cholesterol O acyltransferase Pharmacology Article Brain targeting Chemistry chemistry.chemical_compound chemistry Oral administration Low permeability Nasal administration Solubility QD1-999 Dose conversion
Zdroj:	ACS Omega ACS Omega, Vol 4, Iss 16, Pp 16943-16955 (2019)
ISSN:	2470-1343
Popis:	An acyl-CoA:cholesterol O-acyltransferase-1 (ACAT-1/SOAT-1) inhibitor, K-604 is a promising drug candidate for the treatment of Alzheimer's disease and glioblastoma; however, it exhibits poor solubility in neutral water and low permeability across the blood-brain barrier. In this study, we report the successful delivery of K-604 to the brain via the intranasal route in mice using a hydroxycarboxylic acid solution. In cerebral tissue, the AUC of K-604 after intranasal administration (10 μL; 108 μg of K-604/mouse) was 772 ng·min/g, whereas that after oral administration (166 μg of K-604/mouse) was 8.9 ng·min/g. Thus, the index of brain-targeting efficiency was 133-fold based on the dose conversion. Even with intranasal administration of K-604 once per day for 7 days, the level of cholesteryl esters markedly decreased from 0.70 to 0.04 μmol/g in the mouse brain. Thus, this application will be a crucial therapeutic solution for ACAT-1 overexpressing diseases in the brain.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2fad4fe7cc5ca6aef1b49bda38aade33 http://europepmc.org/articles/PMC6796924 Zobrazit plný text záznamu