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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.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.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.Intranasal delivery of HLS-3 with better pharmacokinetics and pharmacodynamics performances provides a promising approach for treatment of Alzheimer's disease.