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Comparison of the Inhibitory Effects of Clotrimazole and Ketoconazole Against Human Carboxylesterase 2

Author(s):

Tingting Zhao, Dalong Wang, Zhao Shan, Jing Chen, Tongyi Dou, Guangbo Ge, Changyuan Wang, Qiang Meng, Huijun Sun, Kexin Liu and Jingjing Wu*   Pages 1 - 8 ( 8 )

Abstract:


Background: Both clotrimazole and ketoconazole have been verified that they have an inhibitory effect on CYP3A4. hCE2 is an enzyme closely related to the side effects of several anti-cancer drugs. However, the interactions between hCE2 and clotrimazole and ketoconazole remain unclear.

Objective:The objective of this study was to investigate and compare the inhibition behaviors of these two antifungal agents, ketoconazole and clotrimazole, on the human liver microsome hCE2 and to explore the underlying mechanism.

Methods:The inhibitory effects were investigated in human liver microsomes (HLMs) using fluorescein diacetate (FD), N-(2-butyl-1,3-dioxo-2,3-dihydro-1H-phenalen-6-yl)-2-chloroacetamide (NCEN) and irinotecan (CPT-11) as substrates of hCE2.

Results: Clotrimazole significantly inhibited the hCE2 activity, which was manifested by attenuated fluorescence when the substrates were FD and NCEN. The inhibitory effect of clotrimazole towards hCE2 was much stronger than that of ketoconazole, and the inhibitory behaviors displayed substrate-dependent inhibition. The IC50 value of clotrimazole with CPT-11 as the substate increased by 5 and 37 times than that with FD and NCEN respectively. Furthermore, the inhibitions of clotrimazole towards hCE2-mediated hydrolysis of FD, NCEN and CPT-11 were all in competitive mode with the Ki values of 0.483 μM, 8.63 μM and 29.0 μM, respectively. Molecular docking result of clotrimazole binding to hCE2 illustrated that clotrimazole could efficiently orient itself in the Z site cavity of hCE2.

Conclusion:Clotrimazole displayed a strong inhibitory effect against hCE2, which might be used as a potential combined agent co-administrated with CPT-11 to alleviate the hCE2-mediated severe side effects.

Keywords:

imidazole antifungal agents, clotrimazole, ketoconazole, hCE2, CPT-11, drug-drug

Affiliation:

College of Pharmacy, Dalian Medical University, Dalian, 116044, College of Pharmacy, Dalian Medical University, Dalian, 116044, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, School of Life Science and Medicine, Dalian University of Technology,Panjin, 124221, School of Life Science and Medicine, Dalian University of Technology,Panjin, 124221, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, College of Pharmacy, Dalian Medical University, Dalian, 116044, College of Pharmacy, Dalian Medical University, Dalian, 116044, College of Pharmacy, Dalian Medical University, Dalian, 116044, College of Pharmacy, Dalian Medical University, Dalian, 116044, College of Pharmacy, Dalian Medical University, Dalian, 116044



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