UHPLC-HRMS study of pharmacokinetics of a novel hybrid cholinesterase inhibitor K1234: A comparison between in silico, in vitro and in vivo data

Abstract

Alzheimer's disease (AD) is one of the most common forms of dementia. Current anti-AD therapeutics exploit the cholinergic hypothesis of its pathophysiology; they aim to inhibit cerebral cholinesterases. K1234 is a novel hybrid molecule derived from Huperzine A and 7-MEOTA-huperzine which shows increased potency in acetylcholinesterase inhibition in vitro compared to the compounds themselves. The study focused on description of the pharmacokinetic behaviour of K1234, blood-brain barrier penetration, identification of the main in vitro and in vivo metabolites. K1234 is relatively non-toxic compound, that is rapidly absorbed after i.p. administration reaching C_max within minutes, with extensive distribution into tissues and fast metabolism in mice. The dominant metabolic pathway appears to be glucuronidation of the parent molecule and its phase-I metabolites. The passage of K1234 across the blood-brain-barrier in mice appears to be limited, as it reached only approximately one third of the AUC of plasma.

Keywords: Acetylcholinesterase; Alzheimer's disease; Blood-brain-barrier; In silico metabolism prediction; Metabolism; Pharmacokinetics.