E. coli infection modulates the pharmacokinetics of oral enrofloxacin by targeting P-glycoprotein in small intestine and CYP450 3A in liver and kidney of broilers

Mengjie Guo; Yong Sun; Yu Zhang; Shamsuddin Bughio; Xiaohua Dai; Weilong Ren; Liping Wang

doi:10.1371/journal.pone.0087781

E. coli infection modulates the pharmacokinetics of oral enrofloxacin by targeting P-glycoprotein in small intestine and CYP450 3A in liver and kidney of broilers

PLoS One. 2014 Jan 31;9(1):e87781. doi: 10.1371/journal.pone.0087781. eCollection 2014.

Authors

Mengjie Guo¹, Yong Sun¹, Yu Zhang¹, Shamsuddin Bughio¹, Xiaohua Dai², Weilong Ren¹, Liping Wang¹

Affiliations

¹ Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, PR China.
² Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, PR China ; College of Food Science and Pharmacy, Xinjiang Agricultural University, Urumqi, China.

Abstract

P-glycoprotein (P-gp) expression determines the absorption, distribution, metabolism and excretion of many drugs in the body. Also, up-regulation of P-gp acts as a defense mechanism against acute inflammation. This study examined expression levels of abcb1 mRNA and localization of P-gp protein in the liver, kidney, duodenum, jejunum and ileum in healthy and E. coli infected broilers by real time RT-PCR and immunohistochemistry. Meanwhile, pharmacokinetics of orally administered enrofloxacin was also investigated in healthy and infected broilers by HPLC. The results indicated that E. coli infection up-regulated expression of abcb1 mRNA levels significantly in the kidney, jejunum and ileum (P<0.05), but not significantly in the liver and duodenum (P>0.05). However, the expression level of CYP 3A37 mRNA were observed significantly decreased only in liver and kidney of E. coli infected broilers (P<0.05) compared with healthy birds. Furthermore, the infection reduced absorption of orally administered enrofloxacin, significantly decreased Cmax (0.34 vs 0.98 µg mL(-1), P = 0.000) and AUC0-12h (4.37 vs 8.88 µg mL(-1) h, P = 0.042) of enrofloxacin, but increased Tmax (8.32 vs 3.28 h, P = 0.040), T1/2a(2.66 vs 1.64 h(-1), P = 0.050) and V/F (26.7 vs 5.2 L, P = 0.040). Treatment with verapamil, an inhibitor of P-gp, significantly improved the absorption of enrofloxacin in both healthy and infected broilers. The results suggest that the E. coli infection induces intestine P-gp expression, altering the absorption of orally administered enrofloxacin in broilers.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
Animals
Antineoplastic Agents / pharmacology*
Aryl Hydrocarbon Hydroxylases / metabolism*
Avian Proteins / antagonists & inhibitors
Avian Proteins / metabolism*
Chickens
Cytochrome P450 Family 3
Enrofloxacin
Escherichia coli Infections* / drug therapy
Escherichia coli Infections* / metabolism
Escherichia coli Infections* / pathology
Female
Fluoroquinolones / pharmacology*
Intestinal Diseases* / drug therapy
Intestinal Diseases* / metabolism
Intestinal Diseases* / pathology
Intestinal Mucosa / metabolism*
Intestines / pathology
Kidney / metabolism*
Kidney / pathology
Liver / metabolism*
Liver / pathology
Male
Poultry Diseases* / drug therapy
Poultry Diseases* / metabolism
Poultry Diseases* / pathology
Verapamil / pharmacology

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Antineoplastic Agents
Avian Proteins
Fluoroquinolones
Enrofloxacin
Verapamil
Aryl Hydrocarbon Hydroxylases
Cytochrome P450 Family 3
cytochrome P-450 CYP3A37 (chicken)

Grants and funding

The study was supported in part by the National Natural Science Foundation of China (No. 30972220), Natural Science Foundation of Jiangsu Province of China (No. BK2012771), the Fundamental Research Funds for the Central Universities (KYZ201105), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.