Qian_2018_Life.Sci_207_428

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. MAIN METHODS: 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. KEY FINDINGS: 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.