Brain Targeting of Acyl-CoA:Cholesterol O-Acyltransferase-1 Inhibitor K-604 via the Intranasal Route Using a Hydroxycarboxylic Acid Solution
Copyright © 2019 American Chemical Society..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:4 |
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| Enthalten in: |
ACS omega - 4(2019), 16 vom: 15. Okt., Seite 16943-16955 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shibuya, Kimiyuki [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 30.09.2020 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1021/acsomega.9b02307 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM302511741 |
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| 520 | |a Copyright © 2019 American Chemical Society. | ||
| 520 | |a 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 | ||
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| 700 | 1 | |a Miyamoto, Masayoshi |e verfasserin |4 aut | |
| 700 | 1 | |a Ogawa, Shin-Ichiro |e verfasserin |4 aut | |
| 700 | 1 | |a Tsunenari, Yoshihiko |e verfasserin |4 aut | |
| 700 | 1 | |a Urano, Yasuomi |e verfasserin |4 aut | |
| 700 | 1 | |a Noguchi, Noriko |e verfasserin |4 aut | |
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