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    Drug Metabolism and Disposition Fast Forward. Published


    Icotinib induces mechanism-based inactivation of rhCYP3A4/5 possibly via heme destruction by ketene intermediate

    期刊名:Drug Metabolism and Disposition
    文獻地址: https://doi.org/10.1124/dmd.121.000369


    Icotinib (ICT) is an anti-tumor drug approved by China National Medical Products Administration and is found to be effective to conquer non-small cell lung cancer. The present study aimed at the interaction of ICT with CYP3A. ICT exhibited time-, concentration- and NADPH-dependent inhibitory effect on recombinant human CYP3A4/5 (rhCYP3A4/5). About 60% of CYP3A activity was suppressed by ICT at 50 μM after 30 min. The observed enzyme inhibition could not be recovered by dialysis. Nifedipine protected CYP3A from the inactivation by ICT. The inhibitory effects of ICT on CYP3A were neither influenced by GSH/NAL nor by SOD/catalase. Incubation of ICT with human hepatic microsomes produced a ketene reactive intermediate trapped by 4-bromobenzylamine. CYP3A4 dominated the metabolic activation of ICT to the ketene intermediate. Ethyl and vinyl analogs of ICT did not induce inactivation of rhCYP3A4/5, which indicates that acetylenic bioactivation of ICT contributed to the enzyme inactivation. Moreover, the metabolic activation of ICT resulted in heme destruction. In conclusion, this study demonstrated that ICT was a mechanism-based inactivator of rhCYP3A4/5, and heme destruction by the ketene metabolite may be responsible for the observed CYP3A inactivation.

    6β-Hydroxytestosterone was purchased from Chengdu De-Si-Te Biological Technology Co., Ltd (Chengdu, China).
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