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Investigation of ponatinib metabolism and drug-drug interactions with lycopene and shikonin in vitro and invivo.

Investigation of ponatinib metabolism and drug-drug interactions with lycopene and shikonin in vitro and invivo.

Authors :
Chen, Jie
Hong, Fengsheng
Xia, Hailun
Shen, Yuxin
Chen, Xiaohai
Wu, Hualu
Lin, Guanyang
Zhan, Ruanjuan
Source :
Chemico-Biological Interactions. Dec2024, Vol. 404, pN.PAG-N.PAG. 1p.
Publication Year :
2024

Abstract

Ponatinib is approved for use in patients with chronic myeloid leukemia (CML) who are resistant to or intolerant to prior tyrosine kinase inhibitor (TKI) therapy. Given that ponatinib can induce significant cardiotoxicity when taken, and that most Chinese medicines have cardioprotective effects, it is possible to administer them in combination in clinic to alleviate adverse effects. The quantitative determination of ponatinib and its metabolite N-desmethyl ponatinib was optimized and fully verified by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). And the drug-drug interactions (DDI) of ponatinib with lycopene and shikonin, both in vivo and in vitro , were studied. The results of bioanalytical methodology showed that ponatinib and N-desmethyl ponatinib had good linearity in plasma samples, and their selectivity, accuracy, precision, stability, matrix effect and recovery were all satisfied with the need of quantitative analysis of samples. In animal experiments, compared with the control group, lycopene and shikonin significantly changed the pharmacokinetic parameters of ponatinib, including AUC (0-t) , AUC (0-∞) and CL z/F , while having no effect on the pharmacokinetic parameters of N-desmethyl ponatinib. In vitro interaction studies indicated that lycopene showed mixed inhibition mechanism on ponatinib metabolism in both rat liver microsomes (RLM) and human liver microsomes (HLM). And, shikonin displayed mixed inhibition mechanism in RLM and competitive inhibition mechanism in HLM, respectively. In summary, the UPLC-MS/MS method can accurately and sensitively quantify ponatinib and N-desmethyl ponatinib, and provide further reference for clinical drug combination between ponatinib and lycopene or shikonin. • The UPLC-MS/MS analysis method of ponatinib and N -desmethyl ponatinib was verified. • The DDI of ponatinib with lycopene and shikonin was studied for the first time. • Both lycopene and shikonin have inhibitory effects on ponatinib metabolism. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00092797
Volume :
404
Database :
Academic Search Index
Journal :
Chemico-Biological Interactions
Publication Type :
Academic Journal
Accession number :
180678306
Full Text :
https://doi.org/10.1016/j.cbi.2024.111265