title: Screening of drug metabolizing enzymes for fusidic acid and its interactions with isoform-selective substrates in vitro.
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 IC50were 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.
authors: a Department of Clinical Pharmacology , Xiangya Hospital, Central South University , Changsha , Hunan , China.|b Institute of Clinical Pharmacology, Central South University , Changsha , Hunan , China.
authors: D
authors: D
authors: Chen
authors: a Department of Clinical Pharmacology , Xiangya Hospital, Central South University , Changsha , Hunan , China.|b Institute of Clinical Pharmacology, Central South University , Changsha , Hunan , China.
authors: X-X
authors: XX
authors: Lin
authors: a Department of Clinical Pharmacology , Xiangya Hospital, Central South University , Changsha , Hunan , China.|b Institute of Clinical Pharmacology, Central South University , Changsha , Hunan , China.
authors: Q
authors: Q
authors: Zhao
authors: c Department of Pharmacy , Xiangya Hospital, Central South University , Changsha , Hunan , China.
authors: J
authors: J
authors: Xiao
authors: d Department of Hepatology and Infectious Diseases , Xiangya Hospital, Central South University , Changsha , Hunan , China , and.|e Health Management Center, Xiangya Hospital, Central South University , Changsha , Hunan , China.
authors: S-F
authors: SF
authors: Peng
authors: d Department of Hepatology and Infectious Diseases , Xiangya Hospital, Central South University , Changsha , Hunan , China , and.|e Health Management Center, Xiangya Hospital, Central South University , Changsha , Hunan , China.
authors: M-F
authors: MF
authors: Xiao
authors: a Department of Clinical Pharmacology , Xiangya Hospital, Central South University , Changsha , Hunan , China.|b Institute of Clinical Pharmacology, Central South University , Changsha , Hunan , China.
authors: D-S
authors: DS
authors: Ouyang
authors: a Department of Clinical Pharmacology , Xiangya Hospital, Central South University , Changsha , Hunan , China.|b Institute of Clinical Pharmacology, Central South University , Changsha , Hunan , China.
authors: Z-R
authors: ZR
authors: Tan
authors: a Department of Clinical Pharmacology , Xiangya Hospital, Central South University , Changsha , Hunan , China.|b Institute of Clinical Pharmacology, Central South University , Changsha , Hunan , China.
authors: Y-C
authors: YC
authors: Wang
authors: a Department of Clinical Pharmacology , Xiangya Hospital, Central South University , Changsha , Hunan , China.|b Institute of Clinical Pharmacology, Central South University , Changsha , Hunan , China.
authors: J-B
authors: JB
authors: Peng
authors: a Department of Clinical Pharmacology , Xiangya Hospital, Central South University , Changsha , Hunan , China.|b Institute of Clinical Pharmacology, Central South University , Changsha , Hunan , China.
authors: W
authors: W
authors: Zhang
authors: a Department of Clinical Pharmacology , Xiangya Hospital, Central South University , Changsha , Hunan , China.|b Institute of Clinical Pharmacology, Central South University , Changsha , Hunan , China.
authors: Y
authors: Y
authors: Chen
mesh_terms: D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D005672:Fusidic Acid / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic / Q000187:drug effects; D008862:Microsomes, Liver / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D020033:Protein Isoforms; D005672:Fusidic Acid; D003577:Cytochrome P-450 Enzyme System; D019388:Cytochrome P-450 CYP1A2
keywords: Accumulation; CYP2D6; CYP3A4; drug–drug interaction; fusidic acid