Pharmacokinetics, excretion and metabolites analysis of DL0410, a dual‑acting cholinesterase inhibitor and histamine‑3 receptor antagonist

Abstract

DL0410, a dual-action cholinesterase inhibitor and histamine-3 receptor antagonist with a novel structural scaffold, may be a potential candidate for the treatment of Alzheimer's disease (AD). To the best of the authors' knowledge, this is the first study to demonstrate a reliable method for the measurement of DL0410 in rat plasma, brain, bile, urine and feces samples, and identification of its primary metabolites. The pharmacokinetic properties of DL0410 were analyzed by liquid chromatography-mass spectrometry at oral doses of 25, 50 and 100 mg/kg and intravenous dose of 5 mg/kg. The investigation of the excretion and metabolism of DL0410 was determined following liquid-liquid extraction for biliary, urinary and fecal samples. Finally, the cytochrome (CY)P450 isoforms involved in the production of DL0410 metabolites with recombinant human cytochrome P450 enzymes were characterized. The results suggested that DL0410 was not well absorbed; however, was distributed to the entorhinal cortex and hippocampus of the brain. A total of two common metabolites of the reduction of DL0140 in the bile, urine and feces were identified and CYP2D6 was involved in this reaction. The pharmacokinetic results of DL0410 provided information for the illustration of its pharmacodynamic properties, mechanism of action and promoted its continued evaluation as a therapeutic agent for AD treatment.

Histamine H3 receptor and cholinesterases as synergistic targets for cognitive decline: Strategies to the rational design of multitarget ligands

“…The presence of a second ionization site could impair the pharmacokinetic profile of bibasic compounds. Therefore, a pharmacokinetic study with DL0410 was carried out (Pang et al., 2019), indicating a poor oral bioavailability for this compound, but its ability to cross the blood–brain barrier was confirmed. The hydroxy metabolites from carbonyl reduction were also identified.…”