CURRENT DRUG METABOLISM
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2022
·Vol. 23
·期 11
·912-919
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IF 3.408
Wang Zhe,Jiang Lili,Wang Xiaoyu,Yin Hang,Wang Zhen,Lv Xin,Liu Yong
Background: Cabozantinib is a multiple receptor tyrosine kinases inhibitor (TKI) approved to treat progressive, metastatic medullary thyroid cancer, advanced renal cell carcinoma, and hepatocellular carcinoma. Drugdrug interactions (DDIs) for cabozantinib have been identified involving
the role of cytochromes P450. Although the previous study reported that cabozantinib showed a slight inhibition of UDP-glucuronosyltransferase (UGT) 1A1 at the highest concentration tested, there are no reports on the potential for UGTs-mediated-DDIs. Hence, the current study aims to address
this knowledge gap. Objective: This study aimed to investigate the inhibitory effect of cabozantinib on human UGTs and to quantitatively evaluate the DDI potential via UGT inhibition. Methods: The inhibitory effects of cabozantinib on UGTs were determined by measuring the formation
rates for 4- methylumbelliferone (4-MU) glucuronide and trifluoperazine N-glucuronide using recombinant human UGT isoforms in the absence or presence of cabozantinib. Inhibition kinetic studies were conducted to determine the type of inhibition of cabozantinib on UGTs and the corresponding
inhibition constant (Ki) value. In vitro-in vivo extrapolation (IVIVE) was further employed to predict the potential risk of DDI in vivo. Results: Cabozantinib displayed potent inhibition of UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, and 2B15. Cabozantinib exhibited noncompetitive
inhibition towards UGT1A1 and 1A3 and inhibition towards UGT1A7 and 1A9. The Ki,u values (mean ± standard deviation) were calculated to be 2.15±0.11 μM, 0.83±0.05 μM, 0.75±0.04 μM and 0.18 ± 0.10 μM for UGT1A1, 1A3, 1A7 and 1A9, respectively.
Co-administration of cabozantinib at the clinically approved dose of 60 mg/day or 140 mg/day may result in approximately a 26% to 60% increase in the systemic exposure of drugs predominantly cleared by UGT1A9, implying a high risk of DDIs. Conclusion: Cabozantinib has the potential to
cause DDIs via the inhibition of UGT1A9; therefore, additional attention should be paid to the safety of the combined use of cabozantinib and drugs metabolized by UGT1A9.
研究领域:
药理学
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临床医学
·
生物化学
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DOI
PubMed
高影响因子
MOLECULAR DIVERSITY
·
2024
·
IF 3.9
Xie Tianyu,Hu Wenbo,You Lin,Wang Xin
With cabozantinib as the precursor, a novel small molecule inhibitors of c-Met kinase with thieno [2,3- b ] pyridine as the scaffold were designed, synthesized and evaluated for their biological activity against A549, Hela and MCF-7 cell lines. The in vitro activities of 16 compounds were tested by MTT method with cabozantinib as control drug. Most compounds had moderate to strong inhibitory activities on cells. Among them, compound 10 had the strongest inhibitory activity, which was superior to the lead compound cabozantinib. Its IC 50 values for A549, Hela and MCF-7 cells were 0.005, 2.833 and 13.581 μM, respectively. The colony formation assay demonstrated that compound 10 significantly inhibited the colony formation of A549 cells and suppressed their growth in a concentration-dependent manner. The wound healing assay showed that compound 10 could effectively inhibit the migration of cancer cells compared to a blank control group. The AO/EB assay demonstrated that compound 10 possesses the capability to effectively trigger apoptosis in a concentration-dependent manner. The elementary structure–activity relationship, molecular docking and pharmacokinetics studies revealed the significance of thieno [2,3- b ] pyridine derivatives in anti-tumor activity. Graphical abstract
研究领域:
药理学
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肿瘤学
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药物化学
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DOI
PubMed
高影响因子
LUMINESCENCE
·
2022
·Vol. 38
·期 1
·28-38
·
IF 2.613
Xinyue Duan,Dongjing Wang,Yu Liu,Lei Wang,Xiao Wang,Bin Liu
To promote the rational use of cabozantinib (CBZ), this paper studied the influence of several nutritional supplements on the interaction between CBZ and bovine serum albumin (BSA), an appropriate alternative model for human serum albumin (HSA) that is one of the important transporter proteins in plasma, by fluorescence spectroscopy and UV–vis spectroscopy. The results showed that CBZ could quench the fluorescence of BSA via a dynamic–static quenching process, and the six nutritional supplements did not change the quenching mode of BSA by CBZ. However, all of them could reduce the binding constant of the CBZ–BSA system at 293 K and increase the polarity around tryptophan residues. Among them, nicotinamide and vitamin B 12 (VB 12 ) had a greater effect on the binding constants of the CBZ–BSA system. In the meantime, the thermodynamic parameters of the CBZ–BSA system were examined, indicating that the interaction of CBZ with BSA was spontaneous and dominated by hydrophobic forces. Further research discovered that the combining of CBZ with BSA was primarily located within Site I of BSA, and the binding distance r was 2.48 nm. Consequently, while taking CBZ, patients should use VB 12 and nicotinamide carefully, which may interfere with the transport of drugs.
研究领域:
药理学
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生物化学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2025
·
IF 4.7
Bohan Liang,Jiaojiao Ma,Lingmei Wang,Junxia Zhang,Yan Shang,Yanjie Li,Huazhen Zhu,Yunhua Teng,Shiqi Dong,Huirong Fan
Background and purpose This study investigated whether the “RT-PK” phenomenon, referring to radiation therapy's effects on the pharmacokinetics of chemotherapeutic agents, occurs with cabozantinib, a multikinase inhibitor, after radiotherapy and investigated the underlying mechanisms. Method A quantitative liquid chromatography-tandem mass spectrometry method was developed for cabozantinib. Sprague–Dawley (SD) rats were irradiated with X-rays, and changes in cabozantinib distribution and concentration in the blood and excreta were monitored. The RT-PK phenomenon was confirmed, and further studies examined liver injury and alterations in primary metabolic enzymes in rats and HepG2 cells using hematoxylin and eosin staining, flow cytometry, Western blot, quantitative reverse transcription polymerase chain reaction, and serum biochemical analysis. The mRNA expression of IL6/STAT3 and PXR was also determined. Results X-ray exposure increased the area under the drug–time curve (AUC 0-t ) of cabozantinib by 3.6-fold, and excretion of the drug in the feces was 73 % lower in irradiated rats. Hematoxylin and eosin staining showed hepatocyte and interstitial edema, and serum Alanine transaminase and aspartate transaminase contents were decreased. Radiation induced redox imbalance, increased reactive oxygen species and apoptotic markers, and reduced superoxide dismutase and GSH/GSSG contents. As indicated by western blotting and RT-qPCR, the activation of the IL-6/STAT3 pathway reduced PXR expression, leading to decreased levels of CYP450 3A4, the key enzyme that metabolizes cabozantinib. Conclusions Radiation increased reactive oxygen species, activated the IL-6/STAT3 pathway, and inhibited PXR, thereby reducing CYP450 3A4 expression. These changes led to altered cabozantinib metabolism and the “RT-PK” phenomenon.
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DOI
PubMed
高影响因子
PARTICULATE SCIENCE AND TECHNOLOGY
·
2025
·
IF 1.5
Xingwang Sun,Haibin Wu
Ferroptosis, which relies on iron (Fe) ions for the production of reactive oxygen species (ROS), is an effective approach for treating liver cancer. Cells will activate several mechanisms, such as decreasing Fe absorption and sequestering surplus Fe in ferritin, to diminish intracellular Fe levels. This study presents a straightforward, one-pot approach for the fabrication of bovine serum albumin (BS)-stabilized MnFe2O4 (MnFe@BS NPs) intended for liver cancer treatment in ferroptosis therapy. Cabozantinib (CA) and paclitaxel (PA), which can promote ferritin breakdown and augment uptake by elevating transferrin receptor and binding protein IRP2 levels, were encapsulated in MnFe@BS NPs to improve the liver cancer cytotoxic properties. The fabricated MnFe@BS-CA/PA NPs substantially elevate cellular Fe concentration, hence augmenting ROS production within HepG2 cells. Thus, the bimetallic nanozyme demonstrated a synergistic effect of MnFe, CA, and PA, providing a foundation for improving ferroptosis therapy for liver cancer.
研究领域:
纳米医学
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癌症治疗
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仿生材料
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活性氧生物学
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铁死亡研究
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产品关联
DOI
高影响因子
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