Intranasal delivery of a novel acetylcholinesterase inhibitor HLS-3 for treatment of Alzheimer's disease.
Life Sci
; 207: 428-435, 2018 Aug 15.
Article
en En
| MEDLINE
| ID: mdl-29966606
ABSTRACT
AIM:
The present study aims to investigate the pharmacokinetics and pharmacodynamics of HLS-3, a tacrine dimer with high anti-acetylcholinesterase activity for the treatment of Alzheimer's disease. MAINMETHODS:
In vitro Calu-3 and Caco-2 cell monolayer transport and liver microsomal incubation studies of HLS-3 were carried out to evaluate its nasal epithelium and intestinal membrane permeability, transporters involved in absorption and hepatic metabolism. In vivo pharmacokinetics of HLS-3 followed by central and peripheral cholinergic mediated responses and ex vivo AChE activities in rats via oral and intranasal administrations were further investigated and compared. KEYFINDINGS:
Our in vitro studies suggested that HLS-3 is the substrate of both P-gp and MRPs with no significant hepatic oxidation and glucuronidation metabolism. Oral administration only delivered trace amount of HLS-3 in systemic circulation with a high faecal recovery of 70.7%, whereas intranasal administration demonstrated an absolute bioavailability of 28.9% with urinary and faecal recoveries of 1.5% and 34.0%, respectively. In comparison to oral administration of HLS-3, intranasally delivered HLS-3 exhibited significant higher central cholinergic mediated responses without obvious peripheral side effect.SIGNIFICANCE:
Intranasal delivery of HLS-3 with better pharmacokinetics and pharmacodynamics performances provides a promising approach for treatment of Alzheimer's disease.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Acetilcolinesterasa
/
Tacrina
/
Inhibidores de la Colinesterasa
/
Enfermedad de Alzheimer
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Life Sci
Año:
2018
Tipo del documento:
Article