Quercetin On P-gp Mrna And Function In Broilers As Well As Its Effect On Pharmacokinetics Of Oral Enrofloxain In Broilers

The change in transporter expression is an important cause of drug interactions in the clinic,it will affect the drug's concentration and metabolic processes in the body,resulting in adverse effects on drug efficacy and safety.P-glycoprotein(P-glycoprotein,P-gp)belongs to ABC transporter superfamily.It is an energy-dependent drug efflux pump.P-gp takes part in the absorption and excretion of exogenous and endogenous substances,and it can prevent the absorption of harmful substances and promote the elimination of metabolites.Chicken xenobiotic-sensing orphan nuclear receptor(CXR)has the similar structure and function with the nuclear receptor superfamily members.CXR expresses mainly in the liver,small intestine,stomach,kidneys and other organs which is involved in the transcriptional regulation of P-gp expression.Quercetin is a kind of natural flavonoid and recent studies have found that quercetin has a regulation on the pharmacokinetics of some drugs inferred that quercetin may affect the expression of P-gp and CXR.The aim of the studyis to explore the effect of different doses of quercetin(15 and 60 mg/kg)on mdr1 and CXR mRNA expression in live,kidney and intestines in broilers as well as its function on pharmacokinetics of oral enrofloxain.The results of the study will provide a reference for clarifying drug-drug interactions mediated by quercetin.Fristly,real-time RT-RCR was used with ?-actin as house-keeping gene to detect the expression of mdr1 and CXR in tissues of broilers treated by quercetin with different dose(15,60 mg/kg)and times(1,5 and 10 days)The results showed that quercetin(15 and 60 mg/kg)had a very significant induction on the mdr1 mRNA expression in liver by treated for 1?5 and 10 consecutive days(P<0.01);quercetin(15 and 60 mg/kg)could also significantly induce the mdrl mRNA expression in kiedney by treated for 5 and 10 consecutive days(P<0.05).quercetin(15 mg/kg)could significantly inhibit the mdrl mRNA expression in duodenum by treated for one day,but it had different degrees of induced effect on the mdrl mRNA expression in duodenum and jejunum,whereas it wasn't obvious in ileum.Compared with the control group,quercetin(15 and 60 mg/kg)could strongly inhibit the CXR mRNA expression in live,kidney and intestines by treated for 10 consecutive days(P<0.05);And it was strongly inhibited by quercetin treated for 1?5?10 days in jejunum.The CXR mRNA expression was also subject to varying degrees of inhibition in duodenum and ileum.The results suggest that the effect of quercetin on the mdr1 mRNA expression was not possiblely regulated by the route through CXR.Based on the above results,we detected the effect of quercetin on the pharmacokinetics of oral enrofloxacin in broilers.In this study,fifteen healthy broilers were used and randomly divided into three groups,enrofloxacin alone group(oral administration,10 mg/kg)and two quercetin treated group(by 15 and 60 mg/kg for 1 day).The results showed that when the broilers treated with quercetin for one day,the pharmacokinetics of oral enrofloxacin were changed compared with control group.The Cmax and AUC of enrofloxacin decreased while CL and V increased,which indicated that quercetin could improve the efflux of enrofloxacin from intestine.We also use the intestinal perfusion model to study the effect of quercetin on the efflux of Rhodamine 123(Rho123).we took a certain dose of quercetin(15 mg/kg?60 mg/kg)to gavage the broilers for three days with Rhodamine 123 as the probe substrate to study the effect of quercetin on Rho123 tranportation in broilers'jejunum tissues.The experiment results showed that the concentrations of Rho123 in the perfusion fluid of the experiment groups had obvious rising trend compared with the control group;the experiment groups' drug absorption rate constant(Ka)had decreased,the apparent permeability coefficient(Papp)had significantly reduced(P=0.024<0.05,P=0.013<0.05).This study showed that treated with a certain dose of quercetin for a period of time would induce the efflux of P-gp in healthy broiler's jejunum tissues.