The "steric-like" inhibitory effect and mechanism of doxycycline on florfenicol metabolism: Interaction risk

Xiaoqing Xu; Yanan Liu; Mingyue Guo; María-Aránzazu Martínez; Irma Ares; Bernardo Lopez-Torres; María-Rosa Martínez-Larrañaga; Xu Wang; Arturo Anadón; Marta Martínez

doi:10.1016/j.fct.2022.113431

The "steric-like" inhibitory effect and mechanism of doxycycline on florfenicol metabolism: Interaction risk

Food Chem Toxicol. 2022 Nov:169:113431. doi: 10.1016/j.fct.2022.113431. Epub 2022 Sep 15.

Affiliations

¹ National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei, 430070, China; MAO Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
² The State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
³ Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain.
⁴ National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei, 430070, China; MAO Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. Electronic address: wangxu@mail.hzau.edu.cn.
⁵ Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain. Electronic address: aanadon@ucm.es.

PMID: 36116547
DOI: 10.1016/j.fct.2022.113431

Abstract

Most of the studies on doxycycline (DOX) and florfenicol (FF) remain focused on the improvement of antimicrobial activity and antimicrobial spectrum, and there is no relevant report on whether there is interaction between the two drugs after the combination. This research study evaluated the effect of DOX on FF metabolism in vitro and its mechanisms. The findings of this study showed that DOX inhibits FF metabolism in two ways. Firstly, DOX significantly inhibits the expression of CYP3A29, leading to the slower metabolism of FF; secondly, DOX affects the binding of FF to R106 and R372 by competing for the R372 and/or by a "steric-like effect", thus slowing down FF metabolism, which may increase the residual concentration of FF in edible tissues of food producing animals.

Keywords: CYP3A29; Doxycycline; Drug interactions; Florfenicol; Molecular docking; “Steric-like effect”.

MeSH terms

Animals
Anti-Bacterial Agents* / metabolism
Anti-Bacterial Agents* / pharmacology
Binding, Competitive
Cytochrome P-450 CYP3A* / genetics
Cytochrome P-450 CYP3A* / metabolism
Doxycycline* / pharmacology
Drug Interactions
Mutation
Swine
Thiamphenicol* / analogs & derivatives
Thiamphenicol* / metabolism
Thiamphenicol* / pharmacology

Substances

Anti-Bacterial Agents
Cytochrome P-450 CYP3A
Doxycycline
florfenicol
Thiamphenicol