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Xenobiotica
the fate of foreign compounds in biological systems
Volume 47, 2017 - Issue 9
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General Xenobiochemistry

Screening of drug metabolizing enzymes for fusidic acid and its interactions with isoform-selective substrates in vitro

D. ChenDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China, ;Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China,
,
X.-X. LinDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China, ;Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China,
,
Q. ZhaoDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China, ;Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China,
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J. XiaoDepartment of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China,
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S.-F. 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
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M.-F. 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
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D.-S. OuyangDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China, ;Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China,
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Z.-R. TanDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China, ;Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China,
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Y.-C. WangDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China, ;Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China,
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J.-B. PengDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China, ;Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China,
,
W. ZhangDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China, ;Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China,
&
Y. 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 778-784 | Received 18 Jul 2016, Accepted 27 Aug 2016, Published online: 15 Nov 2016
 
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Abstract

1. Fusidic acid (FA) is widely used for the treatment of infections of sensitive osteomyelitis or skin and soft tissue caused by bacteria. However, the role of cytochrome P450s (CYPs) in the metabolism of FA is unclear. In the present study, we screened the main CYPs for the metabolism of FA and studied its interactions with isoform-selective substrates in vitro.

2. The main CYP450s were screened according to the inhibitory effect of specific inhibitors on the metabolism of FA in human liver microsomes (HLMs) or recombinant CYP isoforms. Enzyme kinetic parameters including Ki, Ki′, Vmax, and IC50 were calculated to determine the potential of FA to affect CYP-mediated metabolism of isoform-selective substrates.

3. FA metabolism rate was inhibited by 49.8% and 83.1% under CYP2D6, CYP3A4 selective inhibitors in HLMs. In recombinant experiment, the inhibitory effects on FA metabolism were 83.3% for CYP2D6 and 58.9% for CYP3A4, respectively. FA showed inhibition on CYP2D6 and CYP3A4 with Kis of 13.9 and 38.6 μM, respectively. Other CYP isoforms including CYP1A2, CYP2A6, CYP2C9, CYP2E1, and CYP2C19 showed minimal or no effect on the metabolism of FA.

4. FA was primarily metabolized by CYP2D6 and CYP3A4 and showed a noncompetitive inhibition on CYP2D6 and a mixed competitive inhibition on CYP3A4. Drug–drug interactions between FA and other chemicals, especially with substrates of CYP2D6 and CYP3A4, are phenomena that clinicians need to be aware of and cautious about.

Declaration of interest

This work was supported by the National Scientific Foundation of China (Grants 81302850 and 81300204); the China Postdoctoral Science Foundation (Grants 2013M531817 and 2014T70793); the Science and Technology Plan Projects of Hunan Province (Grant 2014RS4011); and the Changsha Science and Technology Key Project (K1406004-31 and K1308032-31). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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