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

Pang,Xiaocong; Zhao,Ying; Song,Junke; Kang,De; Wu,Song; Wang,Lin; Liu,Ailin; Du,Guanhua

doi:10.3892/mmr.2019.10306

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

Authors:
- Xiaocong Pang
- Ying Zhao
- Junke Song
- De Kang
- Song Wu
- Lin Wang
- Ailin Liu
- Guanhua Du
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Affiliations: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
Published online on: May 28, 2019 https://doi.org/10.3892/mmr.2019.10306
Pages: 1103-1112
Copyright: © Pang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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