Abstract
Harmine (HAR) is a beta-carboline alkaloid widely distributed in nature. It exhibits psychopharmacological effects of improving learning and memory. However, excessive dose of HAR can cause central tremor toxicity, which may be related to the glutamate system. Memantine (MEM) is a non-competitive N-methyl-d-aspartate receptor antagonist. It can be used for the treatment of Alzheimer’s disease and also can block the neurotoxicity caused by glutamate. Therefore, combination of HAR and MEM would be meaningful and the pharmacokinetics investigation of HAR and MEM in combination is necessary. A ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was established and validated for the simultaneous quantitative determination of MEM, HAR and harmol (HOL), a main metabolite of HAR, in rat plasma after oral administration of HAR and MEM in combination (5.0 mg/kg of MEM combined with 20.0, 40.0, 80.0 mg/kg of HAR). The contents of HAR and HOL were determined after oral administration of HAR (20.0, 40.0 and 80.0 mg/kg), and the content of MEM was determined after oral administration of MEM (5.0 mg/kg). Blood samples were collected from each rat at 0 (pre-dose), 0.08, 0.17, 0.25, 0.33, 0.50, 0.75, 1.0, 2.0, 4.0, 8.0, 12.0 and 24.0 h after administration. The maximum peak concentration (Cmax) of MEM was obviously decreased, and the area under the plasma concentration versus time curve from zero to time t (AUC(0-t)) and mean residence time (MRT) were significantly increased after combination with HAR. The Cmax and AUC(0-t) of HAR and its metabolite HOL were increased after combination with MEM. These findings suggested that co-administration of HAR and MEM could extend their residence time in rats, and then might increase the efficacy for treatment of Alzheimer’s disease. Therefore, this study will provide a basis for the rational combined application of HAR and MEM.
Highlights
IntroductionIs a tricyclic beta-carboline alkaloid originally isolated from seeds of Peganum harmala L
The aim of this study is to develop a sensitive and simple ultra-performance liquid chromatography tandem mass spectrometry (UPLC-mass spectrometric (MS)/MS) method for measuring MEM, HAR and harmol (HOL, structure is shown in Figure 1), one of the main metabolites of HAR [34], with tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride hydrate, structure is shown in Figure 1) as an internal standard (IS), and the validated method was applied to explore the pharmacokinetics drug-drug interactions of HAR and MEM in combination
The optimization of UPLC-MS/MS conditions was done by infusing the standard solutions of MEM, HAR, HOL and IS directly into the electrospray ionization (ESI) source
Summary
Is a tricyclic beta-carboline alkaloid originally isolated from seeds of Peganum harmala L. HAR is Molecules 2019, 24, 1430; doi:10.3390/molecules24071430 www.mdpi.com/journal/molecules. Molecules 2018, 23, x FOR PEER REVIEW. Harmine (7-methoxy-1-methyl-9H-pyrido [3,4-β] indole, HAR, structure is shown in Figure 1) is a tricyclic beta-carboline alkaloid originally isolated from seeds of Peganum harmala L. HAR is widely widely distributed in nature, such as various marine creatures, mammalians, human distributed in nature, such as various plants, plants, insects, insects, marine creatures, mammalians, human tissues tissues and body fluids [1]. HAR has been traditionally used for medicinal preparations and ritual and body fluids [1]. HAR has been traditionally used for medicinal preparations and ritual in the in the Middle Central.
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