Article ; Online: Inhibitory effects of the main metabolites of Apatinib on CYP450 isozymes in human and rat liver microsomes.
Toxicology in vitro : an international journal published in association with BIBRA
2023 Volume 95, Page(s) 105739
Abstract: Purpose: The inhibitory effect of Apatinib on cytochrome P450 (CYP450) enzymes has been studied. However, it is unknown whether the inhibition is related to the major metabolites, M1-1, M1-2 and M1-6.: Methods: A 5-in-1 cocktail system composed of ... ...
Abstract | Purpose: The inhibitory effect of Apatinib on cytochrome P450 (CYP450) enzymes has been studied. However, it is unknown whether the inhibition is related to the major metabolites, M1-1, M1-2 and M1-6. Methods: A 5-in-1 cocktail system composed of CYP2B6/Cyp2b1, CYP2C9/Cyp2c11, CYP2E1/Cyp2e1, CYP2D6/Cyp2d1 and CYP3A/Cyp3a2 was used in this study. Firstly, the effects of APA and its main metabolites on the activities of HLMs, RLMs and recombinant isoforms were examined. The reaction mixture included HLMs, RLMs or recombinant isoforms (CYP3A4.1, CYP2D6.1, CYP2D6.10 or CYP2C9.1), analyte (APA, M1-1, M1-2 or M1-6), probe substrates. The reactions were pre-incubated for 5 min at 37 °C, followed by the addition of NAPDH to initiate the reactions, which continued for 40 min. Secondly, IC Results: Under the influence of M1-6, the activity of CYP2B6, 2C9, 2E1 and 3A4/5 was increased to 193.92%, 210.82%, 235.67% and 380.12% respectively; the activity of CYP2D6 was reduced to 92.61%. The inhibitory effects of M1-1 on CYP3A4/5 in HLMs and on Cyp2d1 in RLMs, as well as the effect of M1-2 on CYP3A in HLMs, were determined to be noncompetitive inhibition, with the K Conclusions: M1-1 and M1-2 exhibited inhibition for several CYP450 isozymes, especially CYP2B6, 2C9, 2D6 and 3A4/5. This observation may uncover potential drug-drug interactions and provide valuable insights for the clinical application of APA. |
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MeSH term(s) | Humans ; Rats ; Animals ; Microsomes, Liver/metabolism ; Cytochrome P-450 CYP3A/metabolism ; Cytochrome P-450 CYP2D6/metabolism ; Cytochrome P-450 CYP2D6/pharmacology ; Cytochrome P-450 CYP2E1/metabolism ; Isoenzymes/metabolism ; Cytochrome P-450 CYP2C9/metabolism ; Cytochrome P-450 CYP2B6/metabolism ; NADP/metabolism ; Cytochrome P-450 Enzyme System/metabolism ; Pyridines |
Chemical Substances | Cytochrome P-450 CYP3A (EC 1.14.14.1) ; Cytochrome P-450 CYP2D6 (EC 1.14.14.1) ; apatinib (5S371K6132) ; Cytochrome P-450 CYP2E1 (EC 1.14.13.-) ; Isoenzymes ; Cytochrome P-450 CYP2C9 (EC 1.14.13.-) ; Cytochrome P-450 CYP2B6 (EC 1.14.14.1) ; NADP (53-59-8) ; Cytochrome P-450 Enzyme System (9035-51-2) ; Pyridines |
Language | English |
Publishing date | 2023-12-01 |
Publishing country | England |
Document type | Journal Article |
ZDB-ID | 639064-x |
ISSN | 1879-3177 ; 0887-2333 |
ISSN (online) | 1879-3177 |
ISSN | 0887-2333 |
DOI | 10.1016/j.tiv.2023.105739 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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