| P-glycoprotein, encoded by Abcbl, is an ATP-dependent transporter. It was distributed in cancer cells and normal tissues, which is the most important factor for cancer multi-drug resistance and affecting bioavailability of oral drugs in animals. CYP3A is an important drug metabolizing enzymes. More than 60% of clinical drugs were metabolised by CYP3A, which could be synergic with P-gp to medicate drug-drug interaction in clinic. In recent years, developing low toxicity P-gp inhibitors to improve oral drug bioavailability and reverse the cancer multidrug resistance is a hot research field. Berberine has a good antibacterial activity and had been used for anti-infection drug in clinic. Recently several studies showed that berberine could affect the expression and function of P-gp in rats and some cell lines. However, the effects of berberine on mRNA expression and absorption of drugs in broilers has not been explored and therefore it’s the focous of the study.Fristly, real-time RT-RCR was used with β-actin as house-keeping gene to detect the expression of Abcbl and CYP3A in tissues of broilers treated by berberine with different dose (40,80mg/kg) and times (1,3 and 10days). The results showed that Abcbl could be expressed in all the tested tissues. Especially the expression level is the highest in ileum. Compared with control group, the Abcb1 mRNA level could be significantly increased in liver (P=0.029) when the broilers were treated with low-dose of berberine for 3 consecutive days. But it was significantly inhibited in duodenum (P=0.036, P=0.008), ileum(P=0.026, P=0.003) and kidney (P=0.021,P=0.003)by berberine treated for one day. However, when the chickens were treated by berberine for 10 consecutive days, Abcbl mRNA could not be affected in all tissues. Berberine have no effects on the mRNA expression of CYP3A37 in liver and kidney (P> 0.05). However, the mRNA expression of CYP3A37 in intestinal tissues were significantly inhibited, especially that in duodenum. Further results showed that CXR mRNA expression was inhibited in duodenum (P=0.039, P=0.031) jejunum (P=0.030, P=0.034) and ileum (P=0.015, P=0.012) when the broilers were treated by berberine for one days. Similar with Abcbl mRNA, CXR mRNA in liver (P=0.021, .P=0.038) was increased when the broilers were treated by berberine for 1 day. The results indicated that there exist a correlation between Abcb1 and CXR.In order to explore the effect of berberine on Abcb1 mRNA, we further detected the mRNA changes by different concentrations of berberine in Caco-2 cells. The results showed that the viability of Caco-2 cells could not be significantly decreased when the concentration of berberine less than 200 μM and concentrations of berberine with 20 and 40 μM were chosen in this study. The Abcbl mRNA level could be inhibited when the cells treated by berberine with concentration of 20 and 40 μM for 2,4 and 8 h, resepectively. More than 16 h, the inhibitory effect was not observed significantly.Based on the above results, we finaly detect the effect of berberine on the pharmacokinetics of oral enrofloxacin in broilers. The results showed that when the chickens treated with berberine for one day, the pharmacokinetics of oral enrofloxacin were significantly changed compared with control group. The Ka, T1/2ke and AUC of enrofloxacin were significiantly increased (P<0.05), which indicated that berberine could improve the absorption of enrofloxacin from intestine. The results were coincidental with the Abcbl expression pattern changed by berberine.In conclusion, our results indicated that berberine modulates pharmacokinetics of oral enrofloxacin by targeting P-glycoprotein and CYP450 3A in small intestine in broilers. |
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