氟苯尼考与聚醚类离子载体抗球虫药在肉鸡体内的相互作用初步研究
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摘要
氟苯尼考是一种广泛应用于畜禽和水产养殖业中的氯霉素类新型广谱抗菌药,具有抗菌活性高、不良反应小等特点。氟苯尼考在食品动物体内的药动学和残留研究报道较多,其主要药动学特征是吸收良好、生物利用度高,但代谢产物较多,动物性产品中残留严重。目前,介导氟苯尼考在动物体内的代谢酶及氟苯尼考与其他药物间的相互作用研究的还很少。本实验室前期研究资料显示,CYP3A和P-gp参与了氟苯尼考在兔体内的代谢,CYPIA参与了氟苯尼考在大鼠体内的代谢,而在全球消费量最大的食品动物鸡的体内,氟苯尼考的代谢由哪些酶和蛋白介导、氟苯尼考会不会和养禽业常用的其他药物发生相互作用尚待研究。聚醚类离子载体抗球虫药通常长期添加于饲料中以防控畜禽球虫病。大量研究报道,聚醚类离子载体抗球虫药的某些品种对动物体内的CYP450、b5、AND、AH、EROD、ECON等酶有诱导或抑制作用,对人肿瘤细胞中的P-糖蛋白的基因表达有抑制作用。因此,在使用氟苯尼考来治疗畜禽细菌性疾病感染时,聚醚类离子载体抗球虫药在动物体内的存在就可能与氟苯尼考产生相互作用。为避免药物相互作用带来的不良反应,指导兽医临床上氟苯尼考的合理用药,减少肉鸡可食性组织的药物残留,本试验研究了氟苯尼考与畜禽常用的聚醚类离子载体抗球虫药盐霉素、莫能菌素和马杜霉素在肉鸡体内的相互作用及其机制。具体内容如下：
1.细胞色素CYP4501A、3A以及P-糖蛋白在肉鸡体内氟苯尼考代谢中的作用。
1日龄AA肉鸡饲喂不含任何药物的饲料饲喂至28日龄后,挑选24只健康的雄性肉鸡分为对照组、氟伏沙明处理组、酮康唑处理组和维拉帕米处理组,每组6只。氟伏沙明处理组动物按25mg/kg b.w.t灌服氟伏沙明,1次/天,连续7天,最后一次灌药0.5h后,肉鸡按30mg/kg体重灌服氟苯尼考溶液；酮康唑处理组、维拉帕米处理组、对照组与氟伏沙明处理组操作相同,分别灌服60mg/kg b.w.t的酮康唑、9mg/kg b.w.t的维拉帕米和相同体积的生理盐水。所有肉鸡在灌服氟苯尼考后12h内从翅下静脉采血,高效液相色谱测定氟苯尼考的血药浓度,3P97药动学软件分析药-时数据。结果显示,肉鸡单剂量口服氟苯尼考的药动学过程符合一室开放动力学模型。对照组氟苯尼考的药-时曲线下面积(AUC)和表观清除率(CL/F)分别为13.80±2.18μg/mL-h和2.28±0.34L/kg/h,当体内的CYPIA活性被氟伏沙明特异性抑制后,血浆中氟苯尼考的药时曲线下面积、表观清除率均未发生显著变化(P>0.05)；当体内的CYP3A活性被酮康唑特异性抑制后,血浆中氟苯尼考的药时曲线下面积显著上升了约3倍(35.04±2.11μg/mL·h；P<0.01),表观清除率显著下降到0.86±0.06L/kg/h(P<0.01)；当肉鸡体内P-糖蛋白被特异性抑制后,血浆中氟苯尼考的峰浓度极显著升高,而药-时曲线下面积未发生显著改变。结果表明,CYP3A对氟苯尼考在肉鸡体内的代谢起关键作用,提示在肉鸡疾病防控用药时,为防止药物间相互作用的发生,氟苯尼考应避免和CYP3A的底物、诱导剂和抑制剂联合使用。
2.聚醚类离子载体抗球虫药对氟苯尼考在肉鸡体内药动学的影响。
1日龄AA肉鸡饲喂不含任何药物的饲料饲喂至28日龄后,挑选48只健康雄性肉鸡随机分成对照组、盐霉素诱导组、莫能菌素诱导组和马杜霉素诱导组,每组12只。对照组肉鸡连续14天继续饲喂不含任何药物的饲料；盐霉素诱导组、莫能菌素诱导组和马杜霉素诱导组分别连续14天饲喂含有盐霉素(60mg/kg)、莫能菌素(120mg/kg)和马杜霉素(5mg/kg)的饲料。第15天每组均按30mg/kg体重静脉注射(6只)和经口(6只)灌服氟苯尼考溶液,并分别采集给药后0-10h(静注)和0-24h的血液(口服),用高效液相色谱检测氟苯尼考的血药浓度。结果显示,静注给药后氟苯尼考血药浓度符合二室开放模型,马杜霉素诱导组肉鸡氟苯尼考中央室分布容积(Vc=1.66+0.09L/kg)显著高于对照组(Vc=1.33±0.08L/kg)；盐霉素和马杜霉素诱导组肉鸡的氟苯尼考分布半衰期(t1/2α=0.67±0.05h(SAL),0.62±0.02h(MAD))显著低于对照组(t1/2α=0.86±0.06h)；所有聚醚类离子载体抗球虫药诱导组肉鸡的氟苯尼考消除半衰期(t12β=2.29±0.18h(SAL),2.30±0.05h(MON),2.11±0.06h(MAD))和药时曲线下面积(AUC=24.24±1.97mg·h/L(SAL),23.04±1.43mg·h/L(MON),18.64±0.96mg-h/L(MAD))均显著低于对照组(t1/2β=3.34±0.16h,AUC=29.68±1.58mg·h/L)；莫能菌素和马杜霉素诱导组血浆清除率(CLs=1.33土0.08L/kg·h(MON),1.63±0.08L/kg·h(MAD))显著高于对照组(CLs=1.02±0.05L/kg·h)。口服给药后氟苯尼考血药浓度符合一室开放模型。莫能菌素诱导组肉鸡的吸收半衰期(t1/2kα=0.59±0.06h)、药峰浓度(Cmax=2.93±0.41μg/mL)和峰时(Tmax=1.32±0.08h)显著低于对照组(t1/2kα=1.15±0.11h,Cmax=4.72±0.82gg/mL,Tmax=2.19±0.26h),而血浆表观清除率(CL/F(s)=2.75±0.30L/Kg·h)和表观分布容积(V/F=6.39±1.13L/kg)显著高于对照组(CL/F(s)=1.19±0.16L/kg·h,V/F=3.79±0.94L/kg)；各聚醚类离子载体抗球虫药诱导组的药时曲线下面积(AUC=18.17±1.77mg-h/L,11.94±1.90mg·h/L,19.61±1.65mg-h/L)均显著低于对照组(AUC=26.99土2.85mg·h/L),但仅莫能菌素诱导组的生物利用度(F%=52±8)显著低于对照组(F%=91±10)。提示三种聚醚类离子载体抗球虫药与氟苯尼考之间产生了药物相互作用,因而给饲喂添加含有聚醚类离子载体药物的动物使用氟苯尼考需谨慎。
3.聚醚类离子载体抗球虫药对肉鸡肝脏和小肠氟苯尼考代谢相关基因mRNA表达水平的影响。
1日龄AA肉鸡饲喂不含任何药物的饲料饲喂至28日龄后,挑选24只健康雄性肉鸡随机分成对照组、盐霉素诱导组、莫能菌素诱导组和马杜霉素诱导组,每组6只。对照组肉鸡连续10天继续饲喂不含任何药物的饲料；盐霉素诱导组、莫能菌素诱导组和马杜霉素诱导组分别连续10天饲喂含有盐霉素(60mg/kg)、莫能菌素(120mg/kg)和马杜霉素(5mg/kg)的饲料。采用分光光度法测定肉鸡肝和小肠CYP450和b5的含量,荧光定量PCR检测肉鸡肝和小肠CYP3A37、CXR和MDR1mRNA的表达。荧光定量PCR检测显示,莫能菌素和马杜霉素极显著增加肉鸡肝脏中CYP3A37基因mRNA的含量(P0.01)；盐霉素和马杜霉素则能促进肝脏中CXR基因mRNA的表达(P<0.01,P<0.05),同时还极显著降低肝脏中MDRl基因mRNA含量(P<0.01)。莫能菌素和马杜霉素能诱导肉鸡小肠中CYP3A37基因的mRNA的表达(P<0.01,P<0.05)；三种抗球虫药对小肠中CXR的表达无显著影响；而盐霉素则极显著抑制了小肠中MDR1基因的表达(P<0.01)。结果表明,三种聚醚类离子载体抗球虫药对肉鸡肝脏和小肠中CYP3A37、CXR mRNA的表达有不同程度的诱导作用,对MDR1mRNA的表达有不同程度的抑制作用。三种聚醚类离子载体抗球虫药对肉鸡肝和小肠中CYP3A37及其受体CXR mRNA的表达的影响不一致,提示受体CXR并未参与CYP3A37mRNA的表达调控。
4.聚醚类离子载体抗球虫药对肉鸡肝脏和小肠CYP3A蛋白表达的影响。
1日龄AA肉鸡饲喂不含任何药物的饲料饲喂至28日龄后,挑选24只健康雄性肉鸡随机分成对照组、盐霉素诱导组、莫能菌素诱导组和马杜霉素诱导组,每组6只。对照组肉鸡连续10天继续饲喂不含任何药物的饲料；盐霉素诱导组、莫能菌素诱导组和马杜霉素诱导组分别连续10天饲喂含有盐霉素(60mg/kg)、莫能菌素(120mg/kg)和马杜霉素(5mg/kg)的饲料。以β-actin蛋白为内参,免疫印迹检测对照组和各诱导组肉鸡肝脏和小肠CYP3A蛋白表达的相对量。结果表明,盐霉素、莫能菌素可显著提高肉鸡肝脏组织中CYP450的含量(P<0.05),莫能菌素还可增加肝中b5的含量,而马杜霉素对CYP450含量则无显著影响；三种聚醚类离子载体抗球虫药诱导组肉鸡肝脏中CYP3A蛋白的表达量稍有增加,但统计学上无显著差异(P>0.05)；而这三种聚醚类离子载体抗球虫药均能显著提高肉鸡小肠中CYP3A蛋白的含量(P<0.01)。提示三种聚醚类离子载体抗球虫药对肉鸡肝脏和小肠中CYP3A蛋白的表达的诱导作用存在组织差异性,对小肠中CYP3A蛋白表达的诱导作用是导致聚醚类离子载体抗球虫药与氟苯尼考相互作用的关键因素。兽医临床上联合使用聚醚类离子载体抗球虫药和氟苯尼考等经由CYP3A代谢的药物或其他对CYP3A有诱导或抑制作用的药物时,会产生严重的药物相互作用。
Florfenicol is a newly synthetic broad spectum antibacterial which has high activity and little adverse reaction. Many data of pharmacokinetics and residue of florfenicol in food anmimals have been reported. The absorption property of florfenicol is good and the bioavailability is very high. However, there are many metabolites of florfenicol and the residue of florfenicol is very serious. At present, the studies of the metabolic enzymes and interaction with other drugs in the animal body are very few. The studies of our laboratory have revealed that CYP3A and P-gp are involved in metabolism of florfenicol in rabbits while in rat it was CYP1A mediates its metabolism. It still unknown that which enzymes and proteins mediate the metabolism of florfenicol in chicken and whether interactions will occure between forfenicol and other drugs that widely used in the poultry. Polyether ionophore coccidiostats are chronically added in the feeds husbandary to prevent and cure of coccidiosis. Many research reported that some drugs of this class can induce or inhibit some enzymes such as CYP450, bs, AND, AH, EROD and ECOD in animal body, and can inhibit the express of P-gp of human tumor cells. Therefore, when forfenicol was used to cure animal affection of bacteria, the drug-drug interactions may occure because of the presence of florfenicol. To avoid the adverse reaction resulted from drug-drug interaction, guide veterinary clinical co-administration of florfenicol, and reduce the drug residue of edible tissues of broiler chicken, the drug-drug interactions of florfenicol and three polyether ionophore coccidiostats that widely used in poulty such as salinomycin, monensin and maduramycin, were investigated in this study. The details are as follow:
1. The roles of CYP4501A,3A and P-gp in the metabolism of florfenicol in broiler chickens.
One day old AA broiler chickens are fed drug free feeds until they are28days old. Twenty-four healthy male broilers were randomly divided into four groups in this study and each group has6chickens. The four groups are FFC alone group (control group), FFC+fluvoxomine group (fluvoxomine treated group), FFC+ketoconazole group (ketoconazole treated group) and FFC+verapamil group (verapamil treated group) respectively. For the FFC alone group, saline solution was given the volume as the other groups via p.o. adiminstration once a day for7consecutive days. The other three groups were given via p.o. administration of fluvoxamine (60mg/kg), ketoconazole (25mg/kg) and verapamil (9mg/kg), respectively, once a day for7consecutive days. On the7th day, all chickens were given via p.o. administration at a single dose of30mg/kg of FFC30min post the final administration of saline solution, fluvoxamine, ketoconazole and verapamil. The blood samples were taken from each chicken at time points of0-12h post administration of FFC. The plasma concentration of FFC was detected by high performance liquid chromatography. The pharmacokinetic analysis of FFC was performed using3P97. The results showed that plasma concentration-time data of FFC in chickens was best described by a one-compartment open model. The AUC and CLs of FFC in control group were13.8±2.18μg/mL-h and2.28±0.34L/kg/h, respectively. No significant difference of the AUC and CLs of FFC was found when CYP1A was inhibited by fluvoxomine (P>0.05). However, inhibition of CYP3A by ketoconazole can significantly increase the AUC to3times of that in control group (P<0.01;35.04±2.11μg·/mL·h), and decrease the CL/F of FFC (P<0.0\;0.86±0.06L/kg/h). The Cmax of FFC in the FFC+verapamil group was significantly increased, but the AUC was not changed. These data suggested that CYP3A played a key role, P-gp may be involved and CYP1A was not important in the metabolism of FFC in broiler chickens, implying that the adverse drug-drug interaction may occur in the use of FFC if the the co-administrated drugs are the substrates, inducers or inhibitors of CYP3A or/and P-gp.
2. The effects of polyther ionophore coccidiostas on pharmacokinetics of florfenicol in broiler chickens.
One day old AA broiler chickens are fed drug free feeds until they are28days old. Forty-eight healthy male broilers were randomly divided into four groups in this study and each group has12chickens. The four groups are FFC alone group (control group), FFC+SAL group (SAL induced group), FFC+MON group (MON induced group) and FFC+ MAD group (MAD induced group) respectively. The chickens were fed rations with or without SAL (60mg/kg feeds), MON (120mg/kg feeds) or MAD (5mg/kg feeds) for14consecutive days. FFC was given to the chickens either via intravenously injection (i.v.) or oral administration (p.o.) at a single dose of30mg/kg body weight. The blood samples were taken from each chicken at time points of0-10h (i.v.) and0-24h (p.o.) post administration of FFC. The plasma concentration of FFC was detected by high performance liquid chromatography. The results showed that following i.v. injection the florfenicol plasma concentration declined in a biphasic pattern that can be described by a two-compartment open model. The distribution of center compartment of FFC in MAD induced group chickens (Vc=1.66±0.09L/kg) are higher than the control group (Vc=1.33±0.08L/kg). The distribution half-lives of FFC in SAL or MAD induced group chickens (t1/2α=0.67±0.05h (SAL),0.62±0.02h (MAD)) are lower that the control group (t1/2α=0.86±0.06h). The elimination half-lives (t1/2β=2.29±0.18h (SAL),2.30±0.05h (MON),2.11±0.06h (MAD)) and the area under the drug plasma curve (AUC=24.24±1.97mg-h/L (SAL),23.04±1.43mg-h/L (MON),18.64±0.96mg-h/L (MAD)) of FFC in all the polyether ionophore coccidiostats induced group are lower that the control group (t1/2β=3.34±0.16h, AUC=29.68±1.58mg-h/L). The plasma clearance of FFC in MON and MAD induced group chickens (CLs=1.33±0.08L/kg-h (MON),1.63±0.08L/kg-h (MAD)) are higher than the control gorup (CLs=1.02±0.05L/kg-h). Following p.o. administration the florfenicol plasma concentration can be described adequately by a one-compartment open model. The absorption half-life (t1/2ka=0.59±0.06h), the maximal plasma concentration (Cmax=2.93±0.41μg/mL), and the time of Cmax (Tmax=1.32±0.08h) of FFC in MON induced group chickens are lower than the control group (t1/2ka=1.15±0.11h, Cmax=4.72±0.82μg/mL, Tmax=2.19±0.26h), while the plasma appearance clearance (CL/F(S)=2.15±0.30L/kg-h) and the appearance distribution (V/F=6.39±1.13L/kg) are higher than the control group (CL/F(s)=1.19±0.16L/kg·h, V/F=3.79±0.94L/kg). The area under the drug plasma curve (AUC=18.17±1.77mg-h/L,11.94±1.90mg-h/L,19.61±1.65mg-h/L) of FFC in all the polyether ionophore coccidiostats induced group are lower that the control group (AUC=26.99±2.85mg-h/L) while only the bioavailability of FFC in MON induced group chickens (F%=52±8)is significantly lower than the control group (F%=91±10). It suggests that the drug-drug interactions hve occured between FFC and these three polyether ionophores. Therefore, more attentions should be paid when FFC was used in chicken meanwhile its feed contain the polyether ionophore coccidiostats.
3. The effects of polyther ionophore coccidiostas on mRNA expression of florfenicol metabolic genes in the liver and small intestine of broiler chicken.
One day old AA broiler chickens are fed drug free feeds until they are28days old. Twenty-four healthy male broilers were randomly divided into four groups in this study and each group has6chickens. The four groups are FFC alone group (control group), FFC+SAL group (SAL induced group), FFC+MON group (MON induced group) and FFC+MAD group (MAD induced group) respectively. The chickens were fed rations with or without SAL (60mg/kg feeds), MON (120mg/kg feeds) or MAD (5mg/kg feeds) for10consecutive days. Content of CYP450in the liver and intestine of chicken was measured by spectrophotometry. The mRNA levels of CYP3A37, CXR and MDR1were detected by real-time reverse transcriptase-polymerase chain reaction (Real-time PCR). The results showed that CYP3A37mRNA level of broiler chicken liver was significantly increased by monensin and maduramycin (P<0.01); Salinomycin and maduramycin can significantly facilate the transcription of CXR mRNA (P<0.01, P<0.05) and inhibit the the expression of MDR1(P<0.0\) of chicken liver, monensin and maduramycin can induce the mRNA expression of chicken intestine CYP3A37gene (P<0.01, P<0.05), however, the three polyether ionophore coccidiostats have no significant effect on the CXR expression, while the MDR1expression of intestine was extremely inhibited by salinomycin (P<0.01).
4. The effects of polyther ionophore coccidiostas on CYP3A protein expression in the liver and small intestine of broiler chicken.
One day old AA broiler chickens are fed drug free feeds until they are28days old. Twenty-four healthy male broilers were randomly divided into four groups in this study and each group has6chickens. The four groups are FFC alone group (control group), FFC+SAL group (SAL induced group), FFC+MON group (MON induced group) and FFC+MAD group (MAD induced group) respectively. The chickens were fed rations with or without SAL (60mg/kg feeds), MON (120mg/kg feeds) or MAD (5mg/kg feeds) for10consecutive days. The protein expression of CYP3A was detected by Western blot. The results showed that salinomycin and monensin could increase the content of CYP450of the liver of broiler chickens (P<0.05), but maduramycin could not (P>0.05). Monensin also increased the content of b5of broiler chicken liver. The three drugs could increase protein expression of CYP3A of broiler liver, but there was no statistically defferences (P>0.05). However, they can significantly increase the CYP3A protein expression in boiler intestine (P<0.01). It indicated that serous drug-drug interaction may be occur when polyether ionophore coccidiostats were co-administrated with drugs which metabolished by CYP3A, or/and induced or inhibited CYP3A.
1.细胞色素CYP4501A、3A以及P-糖蛋白在肉鸡体内氟苯尼考代谢中的作用。
1日龄AA肉鸡饲喂不含任何药物的饲料饲喂至28日龄后,挑选24只健康的雄性肉鸡分为对照组、氟伏沙明处理组、酮康唑处理组和维拉帕米处理组,每组6只。氟伏沙明处理组动物按25mg/kg b.w.t灌服氟伏沙明,1次/天,连续7天,最后一次灌药0.5h后,肉鸡按30mg/kg体重灌服氟苯尼考溶液；酮康唑处理组、维拉帕米处理组、对照组与氟伏沙明处理组操作相同,分别灌服60mg/kg b.w.t的酮康唑、9mg/kg b.w.t的维拉帕米和相同体积的生理盐水。所有肉鸡在灌服氟苯尼考后12h内从翅下静脉采血,高效液相色谱测定氟苯尼考的血药浓度,3P97药动学软件分析药-时数据。结果显示,肉鸡单剂量口服氟苯尼考的药动学过程符合一室开放动力学模型。对照组氟苯尼考的药-时曲线下面积(AUC)和表观清除率(CL/F)分别为13.80±2.18μg/mL-h和2.28±0.34L/kg/h,当体内的CYPIA活性被氟伏沙明特异性抑制后,血浆中氟苯尼考的药时曲线下面积、表观清除率均未发生显著变化(P>0.05)；当体内的CYP3A活性被酮康唑特异性抑制后,血浆中氟苯尼考的药时曲线下面积显著上升了约3倍(35.04±2.11μg/mL·h；P<0.01),表观清除率显著下降到0.86±0.06L/kg/h(P<0.01)；当肉鸡体内P-糖蛋白被特异性抑制后,血浆中氟苯尼考的峰浓度极显著升高,而药-时曲线下面积未发生显著改变。结果表明,CYP3A对氟苯尼考在肉鸡体内的代谢起关键作用,提示在肉鸡疾病防控用药时,为防止药物间相互作用的发生,氟苯尼考应避免和CYP3A的底物、诱导剂和抑制剂联合使用。
2.聚醚类离子载体抗球虫药对氟苯尼考在肉鸡体内药动学的影响。
1日龄AA肉鸡饲喂不含任何药物的饲料饲喂至28日龄后,挑选48只健康雄性肉鸡随机分成对照组、盐霉素诱导组、莫能菌素诱导组和马杜霉素诱导组,每组12只。对照组肉鸡连续14天继续饲喂不含任何药物的饲料；盐霉素诱导组、莫能菌素诱导组和马杜霉素诱导组分别连续14天饲喂含有盐霉素(60mg/kg)、莫能菌素(120mg/kg)和马杜霉素(5mg/kg)的饲料。第15天每组均按30mg/kg体重静脉注射(6只)和经口(6只)灌服氟苯尼考溶液,并分别采集给药后0-10h(静注)和0-24h的血液(口服),用高效液相色谱检测氟苯尼考的血药浓度。结果显示,静注给药后氟苯尼考血药浓度符合二室开放模型,马杜霉素诱导组肉鸡氟苯尼考中央室分布容积(Vc=1.66+0.09L/kg)显著高于对照组(Vc=1.33±0.08L/kg)；盐霉素和马杜霉素诱导组肉鸡的氟苯尼考分布半衰期(t1/2α=0.67±0.05h(SAL),0.62±0.02h(MAD))显著低于对照组(t1/2α=0.86±0.06h)；所有聚醚类离子载体抗球虫药诱导组肉鸡的氟苯尼考消除半衰期(t12β=2.29±0.18h(SAL),2.30±0.05h(MON),2.11±0.06h(MAD))和药时曲线下面积(AUC=24.24±1.97mg·h/L(SAL),23.04±1.43mg·h/L(MON),18.64±0.96mg-h/L(MAD))均显著低于对照组(t1/2β=3.34±0.16h,AUC=29.68±1.58mg·h/L)；莫能菌素和马杜霉素诱导组血浆清除率(CLs=1.33土0.08L/kg·h(MON),1.63±0.08L/kg·h(MAD))显著高于对照组(CLs=1.02±0.05L/kg·h)。口服给药后氟苯尼考血药浓度符合一室开放模型。莫能菌素诱导组肉鸡的吸收半衰期(t1/2kα=0.59±0.06h)、药峰浓度(Cmax=2.93±0.41μg/mL)和峰时(Tmax=1.32±0.08h)显著低于对照组(t1/2kα=1.15±0.11h,Cmax=4.72±0.82gg/mL,Tmax=2.19±0.26h),而血浆表观清除率(CL/F(s)=2.75±0.30L/Kg·h)和表观分布容积(V/F=6.39±1.13L/kg)显著高于对照组(CL/F(s)=1.19±0.16L/kg·h,V/F=3.79±0.94L/kg)；各聚醚类离子载体抗球虫药诱导组的药时曲线下面积(AUC=18.17±1.77mg-h/L,11.94±1.90mg·h/L,19.61±1.65mg-h/L)均显著低于对照组(AUC=26.99土2.85mg·h/L),但仅莫能菌素诱导组的生物利用度(F%=52±8)显著低于对照组(F%=91±10)。提示三种聚醚类离子载体抗球虫药与氟苯尼考之间产生了药物相互作用,因而给饲喂添加含有聚醚类离子载体药物的动物使用氟苯尼考需谨慎。
3.聚醚类离子载体抗球虫药对肉鸡肝脏和小肠氟苯尼考代谢相关基因mRNA表达水平的影响。
1日龄AA肉鸡饲喂不含任何药物的饲料饲喂至28日龄后,挑选24只健康雄性肉鸡随机分成对照组、盐霉素诱导组、莫能菌素诱导组和马杜霉素诱导组,每组6只。对照组肉鸡连续10天继续饲喂不含任何药物的饲料；盐霉素诱导组、莫能菌素诱导组和马杜霉素诱导组分别连续10天饲喂含有盐霉素(60mg/kg)、莫能菌素(120mg/kg)和马杜霉素(5mg/kg)的饲料。采用分光光度法测定肉鸡肝和小肠CYP450和b5的含量,荧光定量PCR检测肉鸡肝和小肠CYP3A37、CXR和MDR1mRNA的表达。荧光定量PCR检测显示,莫能菌素和马杜霉素极显著增加肉鸡肝脏中CYP3A37基因mRNA的含量(P0.01)；盐霉素和马杜霉素则能促进肝脏中CXR基因mRNA的表达(P<0.01,P<0.05),同时还极显著降低肝脏中MDRl基因mRNA含量(P<0.01)。莫能菌素和马杜霉素能诱导肉鸡小肠中CYP3A37基因的mRNA的表达(P<0.01,P<0.05)；三种抗球虫药对小肠中CXR的表达无显著影响；而盐霉素则极显著抑制了小肠中MDR1基因的表达(P<0.01)。结果表明,三种聚醚类离子载体抗球虫药对肉鸡肝脏和小肠中CYP3A37、CXR mRNA的表达有不同程度的诱导作用,对MDR1mRNA的表达有不同程度的抑制作用。三种聚醚类离子载体抗球虫药对肉鸡肝和小肠中CYP3A37及其受体CXR mRNA的表达的影响不一致,提示受体CXR并未参与CYP3A37mRNA的表达调控。
4.聚醚类离子载体抗球虫药对肉鸡肝脏和小肠CYP3A蛋白表达的影响。
1日龄AA肉鸡饲喂不含任何药物的饲料饲喂至28日龄后,挑选24只健康雄性肉鸡随机分成对照组、盐霉素诱导组、莫能菌素诱导组和马杜霉素诱导组,每组6只。对照组肉鸡连续10天继续饲喂不含任何药物的饲料；盐霉素诱导组、莫能菌素诱导组和马杜霉素诱导组分别连续10天饲喂含有盐霉素(60mg/kg)、莫能菌素(120mg/kg)和马杜霉素(5mg/kg)的饲料。以β-actin蛋白为内参,免疫印迹检测对照组和各诱导组肉鸡肝脏和小肠CYP3A蛋白表达的相对量。结果表明,盐霉素、莫能菌素可显著提高肉鸡肝脏组织中CYP450的含量(P<0.05),莫能菌素还可增加肝中b5的含量,而马杜霉素对CYP450含量则无显著影响；三种聚醚类离子载体抗球虫药诱导组肉鸡肝脏中CYP3A蛋白的表达量稍有增加,但统计学上无显著差异(P>0.05)；而这三种聚醚类离子载体抗球虫药均能显著提高肉鸡小肠中CYP3A蛋白的含量(P<0.01)。提示三种聚醚类离子载体抗球虫药对肉鸡肝脏和小肠中CYP3A蛋白的表达的诱导作用存在组织差异性,对小肠中CYP3A蛋白表达的诱导作用是导致聚醚类离子载体抗球虫药与氟苯尼考相互作用的关键因素。兽医临床上联合使用聚醚类离子载体抗球虫药和氟苯尼考等经由CYP3A代谢的药物或其他对CYP3A有诱导或抑制作用的药物时,会产生严重的药物相互作用。
Florfenicol is a newly synthetic broad spectum antibacterial which has high activity and little adverse reaction. Many data of pharmacokinetics and residue of florfenicol in food anmimals have been reported. The absorption property of florfenicol is good and the bioavailability is very high. However, there are many metabolites of florfenicol and the residue of florfenicol is very serious. At present, the studies of the metabolic enzymes and interaction with other drugs in the animal body are very few. The studies of our laboratory have revealed that CYP3A and P-gp are involved in metabolism of florfenicol in rabbits while in rat it was CYP1A mediates its metabolism. It still unknown that which enzymes and proteins mediate the metabolism of florfenicol in chicken and whether interactions will occure between forfenicol and other drugs that widely used in the poultry. Polyether ionophore coccidiostats are chronically added in the feeds husbandary to prevent and cure of coccidiosis. Many research reported that some drugs of this class can induce or inhibit some enzymes such as CYP450, bs, AND, AH, EROD and ECOD in animal body, and can inhibit the express of P-gp of human tumor cells. Therefore, when forfenicol was used to cure animal affection of bacteria, the drug-drug interactions may occure because of the presence of florfenicol. To avoid the adverse reaction resulted from drug-drug interaction, guide veterinary clinical co-administration of florfenicol, and reduce the drug residue of edible tissues of broiler chicken, the drug-drug interactions of florfenicol and three polyether ionophore coccidiostats that widely used in poulty such as salinomycin, monensin and maduramycin, were investigated in this study. The details are as follow:
1. The roles of CYP4501A,3A and P-gp in the metabolism of florfenicol in broiler chickens.
One day old AA broiler chickens are fed drug free feeds until they are28days old. Twenty-four healthy male broilers were randomly divided into four groups in this study and each group has6chickens. The four groups are FFC alone group (control group), FFC+fluvoxomine group (fluvoxomine treated group), FFC+ketoconazole group (ketoconazole treated group) and FFC+verapamil group (verapamil treated group) respectively. For the FFC alone group, saline solution was given the volume as the other groups via p.o. adiminstration once a day for7consecutive days. The other three groups were given via p.o. administration of fluvoxamine (60mg/kg), ketoconazole (25mg/kg) and verapamil (9mg/kg), respectively, once a day for7consecutive days. On the7th day, all chickens were given via p.o. administration at a single dose of30mg/kg of FFC30min post the final administration of saline solution, fluvoxamine, ketoconazole and verapamil. The blood samples were taken from each chicken at time points of0-12h post administration of FFC. The plasma concentration of FFC was detected by high performance liquid chromatography. The pharmacokinetic analysis of FFC was performed using3P97. The results showed that plasma concentration-time data of FFC in chickens was best described by a one-compartment open model. The AUC and CLs of FFC in control group were13.8±2.18μg/mL-h and2.28±0.34L/kg/h, respectively. No significant difference of the AUC and CLs of FFC was found when CYP1A was inhibited by fluvoxomine (P>0.05). However, inhibition of CYP3A by ketoconazole can significantly increase the AUC to3times of that in control group (P<0.01;35.04±2.11μg·/mL·h), and decrease the CL/F of FFC (P<0.0\;0.86±0.06L/kg/h). The Cmax of FFC in the FFC+verapamil group was significantly increased, but the AUC was not changed. These data suggested that CYP3A played a key role, P-gp may be involved and CYP1A was not important in the metabolism of FFC in broiler chickens, implying that the adverse drug-drug interaction may occur in the use of FFC if the the co-administrated drugs are the substrates, inducers or inhibitors of CYP3A or/and P-gp.
2. The effects of polyther ionophore coccidiostas on pharmacokinetics of florfenicol in broiler chickens.
One day old AA broiler chickens are fed drug free feeds until they are28days old. Forty-eight healthy male broilers were randomly divided into four groups in this study and each group has12chickens. The four groups are FFC alone group (control group), FFC+SAL group (SAL induced group), FFC+MON group (MON induced group) and FFC+ MAD group (MAD induced group) respectively. The chickens were fed rations with or without SAL (60mg/kg feeds), MON (120mg/kg feeds) or MAD (5mg/kg feeds) for14consecutive days. FFC was given to the chickens either via intravenously injection (i.v.) or oral administration (p.o.) at a single dose of30mg/kg body weight. The blood samples were taken from each chicken at time points of0-10h (i.v.) and0-24h (p.o.) post administration of FFC. The plasma concentration of FFC was detected by high performance liquid chromatography. The results showed that following i.v. injection the florfenicol plasma concentration declined in a biphasic pattern that can be described by a two-compartment open model. The distribution of center compartment of FFC in MAD induced group chickens (Vc=1.66±0.09L/kg) are higher than the control group (Vc=1.33±0.08L/kg). The distribution half-lives of FFC in SAL or MAD induced group chickens (t1/2α=0.67±0.05h (SAL),0.62±0.02h (MAD)) are lower that the control group (t1/2α=0.86±0.06h). The elimination half-lives (t1/2β=2.29±0.18h (SAL),2.30±0.05h (MON),2.11±0.06h (MAD)) and the area under the drug plasma curve (AUC=24.24±1.97mg-h/L (SAL),23.04±1.43mg-h/L (MON),18.64±0.96mg-h/L (MAD)) of FFC in all the polyether ionophore coccidiostats induced group are lower that the control group (t1/2β=3.34±0.16h, AUC=29.68±1.58mg-h/L). The plasma clearance of FFC in MON and MAD induced group chickens (CLs=1.33±0.08L/kg-h (MON),1.63±0.08L/kg-h (MAD)) are higher than the control gorup (CLs=1.02±0.05L/kg-h). Following p.o. administration the florfenicol plasma concentration can be described adequately by a one-compartment open model. The absorption half-life (t1/2ka=0.59±0.06h), the maximal plasma concentration (Cmax=2.93±0.41μg/mL), and the time of Cmax (Tmax=1.32±0.08h) of FFC in MON induced group chickens are lower than the control group (t1/2ka=1.15±0.11h, Cmax=4.72±0.82μg/mL, Tmax=2.19±0.26h), while the plasma appearance clearance (CL/F(S)=2.15±0.30L/kg-h) and the appearance distribution (V/F=6.39±1.13L/kg) are higher than the control group (CL/F(s)=1.19±0.16L/kg·h, V/F=3.79±0.94L/kg). The area under the drug plasma curve (AUC=18.17±1.77mg-h/L,11.94±1.90mg-h/L,19.61±1.65mg-h/L) of FFC in all the polyether ionophore coccidiostats induced group are lower that the control group (AUC=26.99±2.85mg-h/L) while only the bioavailability of FFC in MON induced group chickens (F%=52±8)is significantly lower than the control group (F%=91±10). It suggests that the drug-drug interactions hve occured between FFC and these three polyether ionophores. Therefore, more attentions should be paid when FFC was used in chicken meanwhile its feed contain the polyether ionophore coccidiostats.
3. The effects of polyther ionophore coccidiostas on mRNA expression of florfenicol metabolic genes in the liver and small intestine of broiler chicken.
One day old AA broiler chickens are fed drug free feeds until they are28days old. Twenty-four healthy male broilers were randomly divided into four groups in this study and each group has6chickens. The four groups are FFC alone group (control group), FFC+SAL group (SAL induced group), FFC+MON group (MON induced group) and FFC+MAD group (MAD induced group) respectively. The chickens were fed rations with or without SAL (60mg/kg feeds), MON (120mg/kg feeds) or MAD (5mg/kg feeds) for10consecutive days. Content of CYP450in the liver and intestine of chicken was measured by spectrophotometry. The mRNA levels of CYP3A37, CXR and MDR1were detected by real-time reverse transcriptase-polymerase chain reaction (Real-time PCR). The results showed that CYP3A37mRNA level of broiler chicken liver was significantly increased by monensin and maduramycin (P<0.01); Salinomycin and maduramycin can significantly facilate the transcription of CXR mRNA (P<0.01, P<0.05) and inhibit the the expression of MDR1(P<0.0\) of chicken liver, monensin and maduramycin can induce the mRNA expression of chicken intestine CYP3A37gene (P<0.01, P<0.05), however, the three polyether ionophore coccidiostats have no significant effect on the CXR expression, while the MDR1expression of intestine was extremely inhibited by salinomycin (P<0.01).
4. The effects of polyther ionophore coccidiostas on CYP3A protein expression in the liver and small intestine of broiler chicken.
One day old AA broiler chickens are fed drug free feeds until they are28days old. Twenty-four healthy male broilers were randomly divided into four groups in this study and each group has6chickens. The four groups are FFC alone group (control group), FFC+SAL group (SAL induced group), FFC+MON group (MON induced group) and FFC+MAD group (MAD induced group) respectively. The chickens were fed rations with or without SAL (60mg/kg feeds), MON (120mg/kg feeds) or MAD (5mg/kg feeds) for10consecutive days. The protein expression of CYP3A was detected by Western blot. The results showed that salinomycin and monensin could increase the content of CYP450of the liver of broiler chickens (P<0.05), but maduramycin could not (P>0.05). Monensin also increased the content of b5of broiler chicken liver. The three drugs could increase protein expression of CYP3A of broiler liver, but there was no statistically defferences (P>0.05). However, they can significantly increase the CYP3A protein expression in boiler intestine (P<0.01). It indicated that serous drug-drug interaction may be occur when polyether ionophore coccidiostats were co-administrated with drugs which metabolished by CYP3A, or/and induced or inhibited CYP3A.
引文
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