Potential Pharmacokinetic Drug–Drug Interaction Between Harmine, a Cholinesterase Inhibitor, and Memantine, a Non-Competitive <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-Aspartate Receptor Antagonist
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 &l...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-04-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/24/7/1430 |
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doaj-1834b96c29b44c68bf92e59ddd2a851d |
|---|---|
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Yunpeng Zhang Shuping Li Youxu Wang Gang Deng Ning Cao Chao Wu Wenzheng Ding Yuwen Wang Xuemei Cheng Changhong Wang |
| spellingShingle |
Yunpeng Zhang Shuping Li Youxu Wang Gang Deng Ning Cao Chao Wu Wenzheng Ding Yuwen Wang Xuemei Cheng Changhong Wang Potential Pharmacokinetic Drug–Drug Interaction Between Harmine, a Cholinesterase Inhibitor, and Memantine, a Non-Competitive <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-Aspartate Receptor Antagonist Molecules harmine memantine drug-drug interaction pharmacokinetics Alzheimer’s disease liquid chromatography-mass spectrometry |
| author_facet |
Yunpeng Zhang Shuping Li Youxu Wang Gang Deng Ning Cao Chao Wu Wenzheng Ding Yuwen Wang Xuemei Cheng Changhong Wang |
| author_sort |
Yunpeng Zhang |
| title |
Potential Pharmacokinetic Drug–Drug Interaction Between Harmine, a Cholinesterase Inhibitor, and Memantine, a Non-Competitive <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-Aspartate Receptor Antagonist |
| title_short |
Potential Pharmacokinetic Drug–Drug Interaction Between Harmine, a Cholinesterase Inhibitor, and Memantine, a Non-Competitive <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-Aspartate Receptor Antagonist |
| title_full |
Potential Pharmacokinetic Drug–Drug Interaction Between Harmine, a Cholinesterase Inhibitor, and Memantine, a Non-Competitive <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-Aspartate Receptor Antagonist |
| title_fullStr |
Potential Pharmacokinetic Drug–Drug Interaction Between Harmine, a Cholinesterase Inhibitor, and Memantine, a Non-Competitive <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-Aspartate Receptor Antagonist |
| title_full_unstemmed |
Potential Pharmacokinetic Drug–Drug Interaction Between Harmine, a Cholinesterase Inhibitor, and Memantine, a Non-Competitive <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-Aspartate Receptor Antagonist |
| title_sort |
potential pharmacokinetic drug–drug interaction between harmine, a cholinesterase inhibitor, and memantine, a non-competitive <i>n</i>-methyl-<span style="font-variant: small-caps">d</span>-aspartate receptor antagonist |
| publisher |
MDPI AG |
| series |
Molecules |
| issn |
1420-3049 |
| publishDate |
2019-04-01 |
| description |
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 <i>N</i>-methyl-<span style="font-variant: small-caps;">d</span>-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 (<i>C<sub>max</sub></i>) of MEM was obviously decreased, and the area under the plasma concentration versus time curve from zero to time t (<i>AUC<sub>(0-t)</sub></i>) and mean residence time (<i>MRT</i>) were significantly increased after combination with HAR. The <i>C<sub>max</sub></i> and <i>AUC<sub>(0-t)</sub></i> 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. |
| topic |
harmine memantine drug-drug interaction pharmacokinetics Alzheimer’s disease liquid chromatography-mass spectrometry |
| url |
https://www.mdpi.com/1420-3049/24/7/1430 |
| work_keys_str_mv |
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doaj-1834b96c29b44c68bf92e59ddd2a851d2020-11-24T21:20:56ZengMDPI AGMolecules1420-30492019-04-01247143010.3390/molecules24071430molecules24071430Potential Pharmacokinetic Drug–Drug Interaction Between Harmine, a Cholinesterase Inhibitor, and Memantine, a Non-Competitive <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-Aspartate Receptor AntagonistYunpeng Zhang0Shuping Li1Youxu Wang2Gang Deng3Ning Cao4Chao Wu5Wenzheng Ding6Yuwen Wang7Xuemei Cheng8Changhong Wang9The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Rood, Shanghai 201203, ChinaThe MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Rood, Shanghai 201203, ChinaThe MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Rood, Shanghai 201203, ChinaThe MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Rood, Shanghai 201203, ChinaThe MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Rood, Shanghai 201203, ChinaThe MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Rood, Shanghai 201203, ChinaThe MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Rood, Shanghai 201203, ChinaThe MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Rood, Shanghai 201203, ChinaThe MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Rood, Shanghai 201203, ChinaThe MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Rood, Shanghai 201203, ChinaHarmine (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 <i>N</i>-methyl-<span style="font-variant: small-caps;">d</span>-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 (<i>C<sub>max</sub></i>) of MEM was obviously decreased, and the area under the plasma concentration versus time curve from zero to time t (<i>AUC<sub>(0-t)</sub></i>) and mean residence time (<i>MRT</i>) were significantly increased after combination with HAR. The <i>C<sub>max</sub></i> and <i>AUC<sub>(0-t)</sub></i> 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.https://www.mdpi.com/1420-3049/24/7/1430harminememantinedrug-drug interactionpharmacokineticsAlzheimer’s diseaseliquid chromatography-mass spectrometry |