Effects of fluoroquinolone treatment on MDR1 and MRP2 mRNA expression inEscherichia coli-infected chickens

Abstract

Current knowledge about the expression of ABC transport proteins suggests that their expression is regulated by a variety of factors, including pathological conditions, and in particular inflammatory reactions to infection. As ABC transporters are major determinants of absorption, distribution and excretion of many antimicrobials, modulation of their activity may result in increased or decreased tissue levels of drugs, affecting the efficacy of treatment. As fluoroquinolones have been identified as modulators and substrates of a number of drug transporters, we evaluated the effect of danofloxacin mesylate and enrofloxacin treatment on the levels of expression of MDR1 and MRP2 mRNAs in the intestines and livers of broilers with experimentally induced colibacillosis. MDR1 mRNA expression was significantly decreased in infected animals and was partly restored over 5 days of treatment with orally administered danofloxacin mesylate or enrofloxacin. Changes in the level of expression of MRP2 mRNA were less prominent. The study suggests that the treatment of colibacillosis with fluoroquinolones, which resulted in a significant clinical improvement of the animals, also restored the expression of drug transporters. This is of clinical importance as these ABC transporters significantly contribute to the functionality of important biological barriers, protecting the bird and specific tissues from pathogens and bacterial toxins.

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

“…Single-stranded cDNAs were synthesized and real time PCR was performed, as described previously [16].Negative controls involved omission of RNA from the reverse transcription reactions and amplifications with specific primer/probe sets to confirm the lack of genomic DNA contamination. Primers specific for abcb1 , CYP3A and β-actin were designed as described [1], [17] and commercially synthesized for real-time PCR analysis. Broiler β-actin was chosen as a housekeeping gene for normalization, based on experiments showing stable expression of β-actin mRNA in the small intestine, liver and kidney of broilers.…”

“…Fluoroquinolones have been successfully used to treat colibacillosis in poultry, among which enrofloxacin is most frequently applied [1]. Pharmacokinetic studies of enrofloxacin, which were performed in pets and food-producing animals under healthy conditions via various routes of administration, show that enrofloxacin exhibits good absorption, high bioavailability, large volume of distribution and low protein-binding [2], [3], [4].…”

“…Therefore, there are increasing attentions to the role of P-gp together with CYP450 in veterinary therapy [14]. It is well known that the expression of ABC transport proteins is regulated by a variety of factors, including pathological conditions, and in particular inflammatory reaction to infections [1]. However, it is not well understood whether modulation of their expression may subsequently affect the pharmacokinetics of drugs, altering the efficacy and toxicity of the drugs in animals [1], [14].…”

“…It is well known that the expression of ABC transport proteins is regulated by a variety of factors, including pathological conditions, and in particular inflammatory reaction to infections [1]. However, it is not well understood whether modulation of their expression may subsequently affect the pharmacokinetics of drugs, altering the efficacy and toxicity of the drugs in animals [1], [14]. The pharmacokinetics of enrofloxacin has been extensively studied in broilers [15], but little is known about the relationship between the pharmacokinetics of enrofloxacin and the expression levels of P-gp and CYP450 enzymes in broilers, particularly following E. coli infection.…”

Effect of colibacillosis or coccidiosis on expression of breast cancer resistance protein in small intestine and liver of chickens

“…As intestinal BCRP limits systemic exposure to xenobiotics, alterations in the function and expression of this transporter could account for part of the variation in oral drug absorption. Studies have shown that several factors such as disease (Haritova et al ., ), age (de Zwart et al ., ) and dietary flavonoids (Imai et al ., ; Ahmed‐Belkacem et al ., ) affect the expression levels of BCRP. While expression of BCRP has been extensively investigated in rodent and human tissues, little information is available about its expression in chicken tissues.…”