BIOMEDICAL CHROMATOGRAPHY
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2021
·Vol. 35
·期 11
·e5205
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IF 1.902
Hang Yin,Zhe Wang,Xiaoyu Wang,Xin Lv,Xiaoyu Fan,Mingrui Yan,Yanyan Jia,Lili Jiang,Jun Cao,Yong Liu
Dabrafenib is a novel small molecule tyrosine kinase inhibitor (TKI) which is used to treat metastatic melanoma. The aim of this research was to survey the effects of dabrafenib on human UDP-glucuronosyltransferases (UGTs) and to evaluate the risk of drug–drug interactions (DDIs). The formation rates for 4-methylumbelliferone (4-MU) glucuronide and trifluoperazine-glucuronide in 12 recombinant human UGT isoforms with or without dabrafenib were measured and HPLC was used to investigate the inhibitory effects of dabrafenib on UGTs. Inhibition kinetic studies were also conducted. In vitro–in vivo extrapolation approaches were further used to predict the risk of DDI potentials of dabrafenib via inhibition of UGTs. Our data indicated that dabrafenib had a broad inhibitory effect on 4-MU glucuronidation by inhibiting the activities of UGTs, especially on UGT1A1, UGT1A7, UGT1A8, and UGT1A9, and dabrafenib could increase the area under the curve of co-administered drugs. Dabrafenib is a strong inhibitor of several UGTs and the co-administration of dabrafenib with drugs primarily metabolized by UGT1A1, 1A7, 1A8 or 1A9 may induce potential DDIs.
研究领域:
药理学
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临床医学
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS
·
2022
·Vol. 47
·期 3
·353-361
·
IF 2.569
Wang Zhe,Wang Xiaoyu,Wang Zhen,Fan Xiaoyu,Yan Mingrui,Jiang Lili,Xia Yangliu,Cao Jun,Liu Yong
Background Dabrafenib and irinotecan are two drugs that can be utilized to treat melanoma. A previous in vivo study has shown that dabrafenib enhances the antitumor activity of irinotecan in a xenograft model with unclear mechanism. Objectives This study aims to investigate the inhibition of dabrafenib on SN-38 (the active metabolite of irinotecan) glucuronidation, trying to elucidate the possible mechanism underlying the synergistic effect and to provide a basis for further development and optimization of this combination in clinical research. Methods Recombinant human uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and human liver microsomes (HLMs) were employed to catalyze the glucuronidation of SN-38 in vitro. Inhibition kinetic analysis and quantitative prediction study were combined to predict drug–drug interaction (DDI) potential in vivo. Results Dabrafenib noncompetitively inhibited SN-38 glucuronidation in pooled HLMs and recombinant UGT1A1 with unbound inhibitor constant ( K i,u ) values of 12.43 ± 0.28 and 3.89 ± 0.40 μM, respectively. Based on the in vitro K i,u value and estimation of kinetic parameters, dabrafenib administered at 150 mg twice daily may result in about a 1−2% increase in the area under the curve (AUC) of SN-38 in vivo. However, the ratios of intra-enterocyte concentration of dabrafenib to K i,u ([ I ] gut / K i,u ) are 2.73 and 8.72 in HLMs and recombinant UGT1A1, respectively, indicating a high risk of intestinal DDI when dabrafenib was used in combination with irinotecan. Conclusion Dabrafenib is a potent noncompetitive inhibitor of UGT1A1 and may bring potential risk of DDI when combined with irinotecan.
研究领域:
药理学
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肿瘤学
·
临床药学
✓ 已验证
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
·
2024
·
IF 2.9
Xinyu Tao,Mengting Cheng,Xiangliang Huang,Jiajia Chen,Yunfang Zhou,Ting Liu,Xiaochun Zheng,Nonger Shen,Yiwen Zhang,Peihua Luo,Qiaojun He,Hao Yan,Ping Huang
Lenvatinib is a multi-target inhibitor that exerts anti-tumor effects by inhibiting angiogenesis and is now commonly used as a first-line treatment for hepatocellular carcinoma. However, with the widespread use of lenvatinib, the problem of serious and fatal hepatotoxicity has become increasingly prominent. Currently, the mechanism behind this toxicity is not yet understood, and as a result, there is a lack of safe and effective intervention strategies with minimal side effects. Here, we established the model of lenvatinib-induced liver injury in vivo and in vitro and found that lenvatinib caused hepatotoxicity by inducing apoptosis. Further mechanistic studies in cellular models revealed that lenvatinib upregulated death receptor signaling pathway, which activated the downstream effector Caspase-8, and ultimately led to apoptosis. Meanwhile, lenvatinib-induced apoptosis was associated with ROS generation and DNA damage. In addition, after screening marketed drugs and natural products in combination with cellular modeling, we identified a potential co-administered drug, dabrafenib, which could alleviate lenvatinib-induced hepatotoxicity. Further mechanistic studies revealed that dabrafenib attenuated lenvatinib-induced hepatotoxicity by inhibiting the activation of the death receptor signaling pathway. Subsequently, cancer cell proliferation assays confirmed that dabrafenib did not antagonize the antitumor effects of lenvatinib. In conclusion, our results validate that apoptosis caused by the death receptor signaling pathway is the key cause of lenvatinib-induced hepatotoxicity, and dabrafenib alleviates lenvatinib-induced hepatotoxicity by inhibiting this pathway.
研究领域:
药理学
·
肿瘤学
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2018
·
IF 4.556
Zili Suo,Xinnuo Xiong,Qiaomei Sun,Ludan Zhao,Peixiao Tang,Quan Hou,Yongkui Zhang,Di Wu,Hui Li
Dabrafenib is a novel targeted antimelanoma drug. The present work explored the binding mechanism of dabrafenib-human serum albumin (HSA) and the effect on the esterase-like activity and antioxidant activity of HSA by using 19F NMR, spectroscopy methods, and molecular dynamics simulation. The results of 19F NMR, fluorescence, and time-resolved fluorescence spectroscopy revealed that dabrafenib spontaneously binds to the subdomain IIIA of the HSA by hydrophobic action and forms a static complex. The binding affects the esterase-like activity of HSA but not its antioxidant activity. According to the results of molecular dynamics simulation, dabrafenib interacts with Arg410 and Tyr411, which are the key residue associated with the esterase-like activity of HSA. Meanwhile, dabrafenib does not interact with Cys34, the key residue associated with the antioxidant activity of HSA. The results of circular dichroism spectroscopy and molecular dynamics simulation show that the conformation of HSA is not affected by the binding of dabrafenib. This study can provide useful information for understanding the pharmacokinetic properties of dabrafenib.
研究领域:
药理学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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