Effects of bergapten on the pharmacokinetics of macitentan in rats both in vitro and in vivo
Macitentan was approved by the United States Food and Drug Administration (FDA) in 2013 for the treatment of pulmonary arterial hypertension (PAH). Bergapten is a furanocoumarin that is abundant in Umbelliferae and Rutaceae plants and is widely used in many Chinese medicine prescriptions. Considerin...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-07-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1204649/full |
| _version_ | 1827904825941032960 |
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| author | Jia Xu Quan Zhou Pengjiao Hou Yu Wang Peiwu Geng Zebei Lu Yunfang Zhou Dapeng Dai Shuanghu Wang |
| author_facet | Jia Xu Quan Zhou Pengjiao Hou Yu Wang Peiwu Geng Zebei Lu Yunfang Zhou Dapeng Dai Shuanghu Wang |
| author_sort | Jia Xu |
| collection | DOAJ |
| description | Macitentan was approved by the United States Food and Drug Administration (FDA) in 2013 for the treatment of pulmonary arterial hypertension (PAH). Bergapten is a furanocoumarin that is abundant in Umbelliferae and Rutaceae plants and is widely used in many Chinese medicine prescriptions. Considering the possible combination of these two compounds, this study is aimed to investigate the effects of bergapten on the pharmacokinetics of macitentan both in vitro and in vivo. Rat liver microsomes (RLMs), human liver microsomes (HLMs), and recombinant human CYP3A4 (rCYP3A4) were used to investigate the inhibitory effects and mechanisms of bergapten on macitentan in vitro. In addition, pharmacokinetic parameters were also studied in vivo. Rats were randomly divided into two groups (six rats per group), with or without bergapten (10 mg/kg), and pretreated for 7 days. An oral dose of 20 mg/kg macitentan was administered to each group 30 min after bergapten or 0.5% CMC-Na administration on day 7. Blood was collected from the tail veins, and the plasma concentrations of macitentan and its metabolites were assessed by ultra-performance liquid chromatography - tandem mass spectrometer (UPLC-MS/MS). Finally, we analyzed the binding force of the enzyme and two small ligands by in silico molecular docking to verify the inhibitory effects of bergapten on macitentan. The in vitro results revealed that the IC50 values for RLMs, HLMs, and rCYP3A4 were 3.84, 17.82 and 12.81 μM, respectively. In vivo pharmacokinetic experiments showed that the AUC(0-t), AUC(0-∞), and Cmax of macitentan in the experimental group (20,263.67 μg/L*h, 20,378.31 μg/L*h and 2,999.69 μg/L, respectively) increased significantly compared with the control group (7,873.97 μg/L*h, 7,897.83 μg/L*h and 1,339.44 μg/L, respectively), while the CLz/F (1.07 L/h/kg) of macitentan and the metabolite-parent ratio (MR) displayed a significant decrease. Bergapten competitively inhibited macitentan metabolism in vitro and altered its pharmacokinetic characteristics in vivo. Further molecular docking analysis was also consistent with the experimental results. This study provides a reference for the combined use of bergapten and macitentan in clinical practice. |
| first_indexed | 2024-03-13T00:32:56Z |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-13T00:32:56Z |
| publishDate | 2023-07-01 |
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| spelling | doaj.art-6bc762214fae496baf37289bbb8c88602023-07-10T09:10:46ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-07-011410.3389/fphar.2023.12046491204649Effects of bergapten on the pharmacokinetics of macitentan in rats both in vitro and in vivoJia Xu0Quan Zhou1Pengjiao Hou2Yu Wang3Peiwu Geng4Zebei Lu5Yunfang Zhou6Dapeng Dai7Shuanghu Wang8Department of Pharmacy, The Sencond Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, ChinaThe Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui People’s Hospital, Lishui, Zhejiang, ChinaThe Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, ChinaThe Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui People’s Hospital, Lishui, Zhejiang, ChinaThe Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui People’s Hospital, Lishui, Zhejiang, ChinaThe Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui People’s Hospital, Lishui, Zhejiang, ChinaThe Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui People’s Hospital, Lishui, Zhejiang, ChinaThe Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, ChinaThe Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui People’s Hospital, Lishui, Zhejiang, ChinaMacitentan was approved by the United States Food and Drug Administration (FDA) in 2013 for the treatment of pulmonary arterial hypertension (PAH). Bergapten is a furanocoumarin that is abundant in Umbelliferae and Rutaceae plants and is widely used in many Chinese medicine prescriptions. Considering the possible combination of these two compounds, this study is aimed to investigate the effects of bergapten on the pharmacokinetics of macitentan both in vitro and in vivo. Rat liver microsomes (RLMs), human liver microsomes (HLMs), and recombinant human CYP3A4 (rCYP3A4) were used to investigate the inhibitory effects and mechanisms of bergapten on macitentan in vitro. In addition, pharmacokinetic parameters were also studied in vivo. Rats were randomly divided into two groups (six rats per group), with or without bergapten (10 mg/kg), and pretreated for 7 days. An oral dose of 20 mg/kg macitentan was administered to each group 30 min after bergapten or 0.5% CMC-Na administration on day 7. Blood was collected from the tail veins, and the plasma concentrations of macitentan and its metabolites were assessed by ultra-performance liquid chromatography - tandem mass spectrometer (UPLC-MS/MS). Finally, we analyzed the binding force of the enzyme and two small ligands by in silico molecular docking to verify the inhibitory effects of bergapten on macitentan. The in vitro results revealed that the IC50 values for RLMs, HLMs, and rCYP3A4 were 3.84, 17.82 and 12.81 μM, respectively. In vivo pharmacokinetic experiments showed that the AUC(0-t), AUC(0-∞), and Cmax of macitentan in the experimental group (20,263.67 μg/L*h, 20,378.31 μg/L*h and 2,999.69 μg/L, respectively) increased significantly compared with the control group (7,873.97 μg/L*h, 7,897.83 μg/L*h and 1,339.44 μg/L, respectively), while the CLz/F (1.07 L/h/kg) of macitentan and the metabolite-parent ratio (MR) displayed a significant decrease. Bergapten competitively inhibited macitentan metabolism in vitro and altered its pharmacokinetic characteristics in vivo. Further molecular docking analysis was also consistent with the experimental results. This study provides a reference for the combined use of bergapten and macitentan in clinical practice.https://www.frontiersin.org/articles/10.3389/fphar.2023.1204649/fullpulmonary arterial hypertensionmacitentanbergaptendrug-drug interactionpharmacokinetics |
| spellingShingle | Jia Xu Quan Zhou Pengjiao Hou Yu Wang Peiwu Geng Zebei Lu Yunfang Zhou Dapeng Dai Shuanghu Wang Effects of bergapten on the pharmacokinetics of macitentan in rats both in vitro and in vivo Frontiers in Pharmacology pulmonary arterial hypertension macitentan bergapten drug-drug interaction pharmacokinetics |
| title | Effects of bergapten on the pharmacokinetics of macitentan in rats both in vitro and in vivo |
| title_full | Effects of bergapten on the pharmacokinetics of macitentan in rats both in vitro and in vivo |
| title_fullStr | Effects of bergapten on the pharmacokinetics of macitentan in rats both in vitro and in vivo |
| title_full_unstemmed | Effects of bergapten on the pharmacokinetics of macitentan in rats both in vitro and in vivo |
| title_short | Effects of bergapten on the pharmacokinetics of macitentan in rats both in vitro and in vivo |
| title_sort | effects of bergapten on the pharmacokinetics of macitentan in rats both in vitro and in vivo |
| topic | pulmonary arterial hypertension macitentan bergapten drug-drug interaction pharmacokinetics |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1204649/full |
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