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Xenobiotica
the fate of foreign compounds in biological systems
Volume 48, 2018 - Issue 10
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General Xenobiochemistry

The potent mechanism-based inactivation of CYP2D6 and CYP3A4 with fusidic acid in in vivo bioaccumulation

Xiu-Xian LinDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China, ;Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China,
,
Guang-Hui LianDepartment of gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan, China,
,
Ying XuDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China, ;Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China,
,
Qing ZhaoDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China, ;Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China,
,
Jian XiaoDepartment of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China,
,
Shi-Fang PengDepartment of Hepatology and Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, China, and ;Health Management Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
,
Mei-Fang XiaoDepartment of Hepatology and Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, China, and ;Health Management Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
,
Dong-Sheng OuyangDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China, ;Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China,
,
Zhi-Rong TanDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China, ;Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China,
,
Yi-Cheng WangDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China, ;Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China,
,
Jing-Bo PengDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China, ;Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China,
,
Wei ZhangDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China, ;Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China,
&
Yao ChenDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China, ;Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China, Correspondence[email protected]
 show all
Pages 999-1005 | Received 05 Sep 2017, Accepted 06 Oct 2017, Published online: 10 Nov 2017
 
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Abstract

1. The accumulation of fusidic acid (FA) after multiple doses of FA has been reported on in previous studies but the related mechanisms have not been clarified fully. In the present study, we explain the mechanisms related to the mechanism-based inactivation of CYP2D6 and CYP3A4.

2. The irreversible inhibitory effects of FA on CYP2D6 and CYP3A4 were examined via a series of experiments, including: (a) time-, concentration- and NADPH-dependent inactivation, (b) substrate protection in enzyme inactivation and (c) partition ratio with recombinant human CYP enzymes. Metoprolol α-hydroxylation and midazolam 1′-hydroxylation were used as marker reactions for CYP2D6 and CYP3A4 activities, and HPLC-MS/MS measurement was also utilised.

3. FA caused to the time- and concentration-dependent inactivation of CYP2D6 and CYP3A4. About 55.8% of the activity of CYP2D6 and 75.8% of the activity of CYP3A4 were suppressed after incubation with 10 μM FA for 15 min. KI and kinact were found to be 2.87 μM and 0.033 min−1, respectively, for CYP2D6, while they were 1.95 μM and 0.029 min−1, respectively, for CYP3A4. Inhibition of CYP2D6 and CYP3A4 activity was found to require the presence of NADPH. Substrates of CYP2D6 and CYP3A4 showed that the enzymes were protected against the inactivation induced by FA. The estimated partition ratio for the inactivation was 7 for CYP2D6 and 12 for CYP3A4.

4. FA is a potent mechanism-based inhibitor of CYP2D6 and CYP3A4, which may explain the accumulation of FA in vivo.

Declaration of interest

The authors declare that no competing interests exist.

This work was supported by the National Science and Technology Plan [Grant SQ2017ZX090361], the National Scientific Foundation of China [Grant 81302850], the Changsha Science and Technology Plan [Kq1602014] and the Fundamental Research Fund for the Central South University [2016zzts512]. The funding bodies played no role in the study design, the data collection or the data analysis. Similarly, it was the researchers’ sole decision to publish the results and to prepare this manuscript.

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