氟苯尼考在家兔体内的代谢机制及药物间相互作用的研究
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摘要
氟苯尼考是一种新型的动物专用广谱抗菌药,它在治疗家畜、家禽以及鱼类的细菌感染等方面具有良好的疗效。虽然氟苯尼考已被广泛用于治疗和预防畜禽及水产养殖业的疾病,但是对氟苯尼考在家兔体内代谢机制的研究还非常有限。了解氟苯尼考在动物体内的代谢模式和调控机制,对有效地控制食品动物食用组织的药物残留以及避免临床联合用药时的药物间相互作用具有非常重要的临床意义。本文对氟苯尼考在家兔体内的代谢机制和药物间相互作用的研究主要从以下5个方面进行探讨：
1.氟苯尼考在家免体内的药代动力学特征和口服生物利用度的研究氟苯尼考对治疗家兔的胃肠道和呼吸道感染具有良好的疗效,同时它也是治疗家兔巴氏杆菌病的首选药物。但是关于家兔静脉注射氟苯尼考的药代动力学特征及口服生物利用度的研究资料在国内还未见报道。本试验采用10只健康的雄性新西兰白兔,分为口服给药组和静脉注射给药组。口服给药组动物按25mg/kg体重灌服氟苯尼考,静脉注射给药组动物按25mg/kg体重耳缘静脉注射氟苯尼考。两组动物在给药后12h内收集右侧耳缘静脉血液,用高效液相色谱测定家兔口服和静脉注射氟苯尼考的血药浓度变化,用3P97药代动力学软件处理药时数据。研究结果表明：家兔口服和静脉注射氟苯尼考的药代动力学特征符合一室开放模型。静脉注射氟苯尼考药代动力学参数：零时血药浓度(Co)、消除速率常数(Ke)、中心室分布容积(Vc)、消除半衰期(T1/2Ke).药-时曲线下面积(AUC)、表观清除率(CL/F)的结果分别是22.58±5.53μg/m.0.55±0.07h-1、1.31±0.21L/kg.1.33±0.16h、40.06±6.07μg·mL-1·h、0.68±0.10L/kg/h.家兔口服氟苯尼考后,血浆中药物的消除相与Y轴的截距(A)、Ke、吸收速率常数(Ko)、滞留时间(Lag time).吸收半衰期(T1/2Ka)、T1/2Ke、达峰时间(Tmax)、达峰浓度(Cmax)、AUC、CL/F和表观分布容积(V/F)分别为10.21±4.13μg/mL,0.37±0.08h-1,1.17±0.23h-1,0.09±0.04h,0.71±0.16h,2.20±0.42h,1.62±0.24h,2.45±0.46μg/mL,12.26±2.21μg·mL-1·h,2.25±0.30L/kg/h,7.41±2.06L/Kg.家兔口服氟苯尼考的生物利用度(F)为(46.83±4.92)%。此结果提示,氟苯尼考的口服生物利用度较低,静脉注射途径能达到较好的治疗效果。
2.比较研究GYP450酶对氟苯尼考在家兔和大鼠上代谢特征的差异15只雄性大鼠,分为氟苯尼考单剂量组、氟伏沙明处理组和酮康唑处理组。氟苯尼考单剂量组动物按100mg/kg体重灌服氟苯尼考；氟伏沙明处理组按60mg/kg体重连续3天灌胃氟伏沙明,一天一次,连续三天,在第三天最后一次给药后30min,动物按100mg/kg体重灌服氟苯尼考；酮康唑处理组的动物与氟伏沙明处理组相同,只是按75mg/kg体重连续3天灌服酮康唑。15只健康的雄性新西兰白兔分为氟苯尼考单剂量组、氟伏沙明处理组和酮康唑处理组。氟苯尼考单剂量组动物灌服25mg/kg体重氟苯尼考；氟伏沙明处理组动物每天按25mg/kg体重灌服氟伏沙明,一天一次,连续3天,在最后一次灌胃氟伏沙明后30min,按25mg/kg体重给家兔灌胃氟苯尼考；酮康唑处理组动物与氟伏沙明处理组相同,按60mg/kg体重连续3天灌服酮康唑。每组动物在氟苯尼考灌服后12h内收集静脉血液,用高效液相色谱测定氟苯尼考的血药浓度变化,3P97药代动力学软件处理药时数据。结果表明：大鼠单剂量口服氟苯尼考的药代动力学分布特征符合一室开放动力学模型。大鼠的CYPIA活性：被氟伏沙明特异性抑制后,血浆中氟苯尼考的Cmax、AUC显著升高(P<0.05),CL/F和V/F显著降低(P<0.05)。大鼠体内的CYP3A活性被酮康唑特异性抑制后,氟苯尼考各个药代动力学参数没有发生显著的变化(P>0.05)。家兔的研究结果表明：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AUC值高达对照组的3倍(P<0.05), CL/F显著降低到原来的1/3(P<0.01)。但是,当体内的CYPIA活,性被氟伏沙明特异性抑制后,血浆中氟苯尼考的各个药代动力学参数均未发生显著变化(P>0.05)。这些结果表明氟苯尼考在不同的动物中是经过不同的CYP450亚型代谢的。CYPIA在大鼠的氟苯尼考代谢中发挥了重要作用,而CYP3A在家兔的氟苯尼考代谢中起主要代谢作用。
3.P-糖蛋白在家兔氟苯尼考口服代谢中的作用用P-糖蛋白的特异性抑制剂维拉帕米研究了P-糖蛋白在家兔氟苯尼考口服代谢中的作用。10只健康的雄性新西兰白兔分为氟苯尼考对照组和维拉帕米处理组。氟苯尼考对照组按25mg/kg体重口服单剂量氟苯尼考。维拉帕米处理组在按9mg/kg体重口服维拉帕米后30min,按25mg/kg体重灌服单剂量的氟苯尼考。用高效液相色谱检测血浆中氟苯尼考的浓度,3P97药代动力学软件处理药时数据。结果表明：氟苯尼考单剂量组动物血浆中氟苯尼考的Ke和T1/2Ke分别为0.37±0.08h-1和2.20±0.42h。维拉帕米特异性抑制了体内的P-糖蛋白后,氟苯尼考的Ke(0.13±0.04h-1)显著降低(P<0.05),T1/2Ke(8.85±2.68h)显著升高(P<0.05),AUC (35.78±5.55μg·mL-1·h)比氟苯尼考单剂量组显著增高了3倍,CL/F(0.75±0.09L/kg/h)是氟苯尼考单剂量组的1/3。这些结果表明：P-糖蛋白在家兔氟苯尼考的口服代谢中发挥了重要作用,抑制P-糖蛋白会导致体内氟苯尼考的生物利用度升高。因此当氟苯尼考与P-糖蛋白的底物、抑制剂或者诱导剂联合用药时,可能会发生药物的相互作用。
4.恩诺沙星对家免氟苯尼考代谢的药代动力学特征的影响。10只新西兰白兔分为氟苯尼考对照组和恩诺沙星处理组。氟苯尼考对照组动物按25mg/kg体重静脉注射单剂量的氟苯尼考；恩诺沙星处理组动物按10mg/kg体重连续静脉注射恩诺沙星3天,在最后一次恩诺沙星给药后15min,动物按25mg/kg体重静脉注射氟苯尼考。在氟苯尼考给药后12h内收集耳缘静脉的血液,用高效液相色谱分析氟苯尼考的药代动力学变化,3P97药代动力学软件处理药时数据。结果表明：恩诺沙星连续处理家兔后,氟苯尼考的药代动力学参数,如AUC、消除半衰期(T1/2β)和内在清除率(CL)等均没有发生显著的变化。这提示临床上家兔按常规剂量连续使用恩诺沙星不会对氟苯尼考的代谢产生药代学影响,恩诺沙星对药物代谢酶的抑制作用可以忽略。
5.氟苯尼考和恩诺沙星对家免肝脏、肾脏和十二指肠的CYP3A6mRNA和CYP3A蛋白表达的影响。12只雄性新西兰白兔分为空白对照组、氟苯尼考处理组和恩诺沙星处理组。空白对照组动物不给予任何药物；氟苯尼考处理组动物按25mg/kg体重灌胃氟苯尼考连续3天。恩诺沙星处理组动物按10mg/kg体重连续灌服恩诺沙星3天,第4天在无菌条件下开胸取出动物的肝脏、肾脏以及十二指肠。提取三种组织的RNA和微粒体蛋白进行RT-PCR和Weatern blot试验。RT-PCR的结果表明,氟苯尼考对家兔CYP3A6的nRNA表达的影响具有组织特异性。连续灌服氟苯尼考能显著的诱导家兔肝脏CYP3A6mRNA的表达(P<0.05),抑制肾脏CYP3A6mRNA的表达(P<0.05),对十二指肠的CYP3A6的表达则没有显著影响(P>0.05)。恩诺沙星能显著的抑制家兔肝脏CYP3A6mRNA的表达(P<0.05),对十二指肠和肾脏的CYP3A6表达没有显著的抑制作用(P>0.05)。Western blot结果显示,氟苯尼考对家兔十二指肠的CYP3A蛋白表达具有显著的诱导作用(P<0.05),但对肾脏和肝脏的CYP3A蛋白表达没有显著作用。恩诺沙星对家兔的肝脏、肾脏和十二指肠的CYP3A蛋白表达均缺乏显著的诱导或抑制作用。
Florfenicol (FFC) is a synthetic broad-spectrum antibiotic in animals. Although it has been widely used in livestock, poultry and carp, the primary enzymes that are involved in the FFC metabolism remains to be defined. Understanding of the metabolism mechanism of FFC is important for avoiding the possible adverse drug-drug interactions and reducing the drug residue in the edible tissues. The aim of the present study was to investigate the metabolism mechanism of FFC and drug-drug interaction. The details are divided into five parts as follows:
To investigate the pharmacological (PK) disposition of FFC, Ten white healthy Newland rabbits were used and randomly allocated into two groups (i.v. or p.o. administration) of five animals each. Aqueous solutions of FFC were administered by i.v. and p.o. route at single doses of25mg/kg b.w. Blood samples were collected in the12h. The plasma concentration of FFC was determined by HPLC system. The pharmacological data analysis was performed by3P97. The results showed that the data of pharmacological parameters were fitted to one-compartment open models follow p.o. and i.v. routes of administration. For the i.v. route, the plasma drug concentration from zero (Co)22.58±5.53μg/mL, elimination rate constant (Ke)0.55±0.07h-1, volume of distribution at steady-state (Vc)1.31±0.21L/kg, half-lives of elimination phase (T1/2Ke)1.33±0.16h, area under curve (AUC)40.06±6.07and apparent body clearance (CLIF)0.68±0.10L/kg/h. For the p.o. route, the intercepts of elimination phases with Y-axis (A)10.21±4.13μg/mL, apparent body clearance (CL/F)0.68±0.10L/kg/h, the elimination rate constant (Ke)0.37±0.08h-1, the absorbtiong rate constant1.17±0.23h-1, lag time0.09±0.04h, half-lives of absorption phase(T1/2Ka)0.71±0.16h, half-lives of elimination phase (T1/2Ke)2.20±0.42h, The maximum plasma concentration (Cmax)2.45±0.46μg/mL, the time of occurrence of Cmax (Tmax)1.62±0.24h, area under curve (AUC)12.26±2.21μg·mL-1·h and apparent distribution of volumn (V/F)7.41±2.06L/kg. The oral bioavailability (F) of FFC was (46.83±4.92)%. Further studies are necessary to identify the range of MIC values for rabbit pathogens and to identify the most appropriate PK-PD parameter needed to predict an effective dose.
Comparatively little is known about the ability of CYP450in the metabolism of FFC with rabbits and rats. Fifteen SD rats were used and divided into three groups in this study. They are FFC alone group, FFC+fluvoxomine-treatment group and FFC+ketoconazole-treatment group, repeactively. For the FFC alone group, FFC was given at a single p.o. dose of100mg/kg.The other two groups were given after p.o. administration of60mg/kg of fluvoxamine and75mg/kg of ketoconazole, respectively, once a day for three days consecutively. On the third day, the animals were given at a single p.o. dose of100mg/kg of FFC30min after the final administration of fluvoxamine or ketoconazole. Fifteen white male New Zealand rabbits were used in this study. The animals were divided into three groups (n=5, each group). For the FFC alone group, FFC was given at the dose of25mg/kg. The other two groups were given after p.o. administration of25mg/kg of fluvoxamine and60mg/kg of ketoconazole, respectively, once a day for three days consecutively. On the third day, the animals were given at a single p.o. dose of25mg/kg of FFC30min after the final administration of fluvoxamine or ketoconazole. The plasma concentration of FFC was analyzed by HPLC system. The mobile phase consisted of a mixture of acetonitrile-water at a ratio of75:25(v/v) and adjusted to pH of2.8with phosphate buffer. The pharmacokinetic analysis of FFC was performed using3P97. The results in rats showed that plasma concentration-time data of FFC was best described by a one-compartment open model. Inhibition of CYP1A activity significant increased the Cmax and AUC of FFC in rats (P<0.05). At the same time, the CLIF and VIF of FFC was significantly decreased compared with FFC Alone group (P<0.05). However, Inhibition of CYP3A activity did not alter the pharmacological disposition of FFC in rats. In rabbits, we found that the deposition of FFC was best described by a one-compartmental open model. We found that inhibition of CYP3A activity significantly increased the AUC and decreased the CLIF of FFC, respectively, but not in the FFC+fluvoxamine group. These suggested that the adverse drug-drug interaction in the use of FFC may occur if the substrates, inducers or inhibitors of CYP3A of the same metabolism mechanism are co-administrated in rabbits. These results suggested that CYP450enzyme play the different role in the metabolism of FFC in the different animals. For the rats, CYP1A was involved in the metabolism of FFC while CYP3A was involved in the metabolism of FFC of rabbits.
To evaluate the role of P-gp in the metablism of FFC, here we employed verapamil (P-gp inhibitor) to investigate the role of P-gp in the PK disposition of FFC. Ten white male New Zealand rabbits (-2kg) were used in this study. The animals were divided into two groups (n=5, each group). For the saline control group, FFC was given at a single p.o. dose of25mg/kg b.w. via nasogastric tube. For the verapamil+FFC group, FFC was administrated as described above,30min after a single p.o. administration of9mg/kg of verapamil. The plasma concentration of FFC was analyzed by HPLC system. The results showed that the deposition of FFC was best described by a one-compartmental open model. We found that inhibition of P-gp significantly increased the AUC and decreased the CL/F of FFC, respectively. Furthermore, a significant decrease of Ke was observed, while an evident increase of T1/2Ke was found. These suggested that the adverse drug-drug interaction in the use of FFC may occur if the substrates, inducers or inhibitors (P-gp or/and CYP3A of the same metabolism mechanism are co-administrated.
To investigat the possible drug-drug interaction between FFC and Enrofloxacin (ENR), ten healthy Newland rabbits weighting～2kg were used and divided to two groups in this study. For the FFC alone group, FFC was given at the intravenous dose of25mg/kg. For the ENR group, the ENR was given at the i.v. dose10mg/kg for three days consecutively. On the third day, the FFC was administrated at the dose of25mg/kg15min after final dose of ENR. Plasma FFC concentration was analysised by HPLC system. The result showed that the PK parameters of FFC, such as A UC, CL and T1/2β, were not changed after administration of ENR in rabbits. This indicated that the inhibitory effect of ENR on disposition of FFC was absent at clinical dosage in vivo in rabbits.
To evaluate the effect of FFC on CYP3A6mRNA and CYP3A protein expression in rabbits, twelve white male New Zealand rabbits were used in this study. The animals were divided into three groups (n=4, each group). For the control group, the animals were not given any drug. For the FFC group, FFC was given at the oral dose of25mg/kg b.w. via nasogastric tube for consecutive three days. For the ENR group, ENR was administrated at the oral dose of10mg/kg for consecutively three days. All the animals were killed2h after the last dose, and the liver, kidney and duodenum were collected immediately. The results of RT-PCR showed that the expression of FFC were specific in the different tissue of rabbits. We found that the expression of CYP3A6mRNA was induced in the liver (P<0.05) while it was inhibited in the kidney of rabbits (P<0.05) for the FFC group, but not in the duodenum (P>0.05). On the other hands, CYP3A6mRNA was inhibited in the liver of rabbits for the ENR group, but not in the kidney or duodenum (.P>0.05). The results of Western blot showed that the expression of CYP3A protein was induced by the FFC in the duodenum(P<0.05), but not in the liver and kidney. CYP3A protein was not induced or inhibited by ENR in the liver, kidney and duodenum(P>0.05). It may be useful in the veterinary clinics when the substrates, inducers or inhibitors of CYP3A enzymes are co-administrated with FFC.
1.氟苯尼考在家免体内的药代动力学特征和口服生物利用度的研究氟苯尼考对治疗家兔的胃肠道和呼吸道感染具有良好的疗效,同时它也是治疗家兔巴氏杆菌病的首选药物。但是关于家兔静脉注射氟苯尼考的药代动力学特征及口服生物利用度的研究资料在国内还未见报道。本试验采用10只健康的雄性新西兰白兔,分为口服给药组和静脉注射给药组。口服给药组动物按25mg/kg体重灌服氟苯尼考,静脉注射给药组动物按25mg/kg体重耳缘静脉注射氟苯尼考。两组动物在给药后12h内收集右侧耳缘静脉血液,用高效液相色谱测定家兔口服和静脉注射氟苯尼考的血药浓度变化,用3P97药代动力学软件处理药时数据。研究结果表明：家兔口服和静脉注射氟苯尼考的药代动力学特征符合一室开放模型。静脉注射氟苯尼考药代动力学参数：零时血药浓度(Co)、消除速率常数(Ke)、中心室分布容积(Vc)、消除半衰期(T1/2Ke).药-时曲线下面积(AUC)、表观清除率(CL/F)的结果分别是22.58±5.53μg/m.0.55±0.07h-1、1.31±0.21L/kg.1.33±0.16h、40.06±6.07μg·mL-1·h、0.68±0.10L/kg/h.家兔口服氟苯尼考后,血浆中药物的消除相与Y轴的截距(A)、Ke、吸收速率常数(Ko)、滞留时间(Lag time).吸收半衰期(T1/2Ka)、T1/2Ke、达峰时间(Tmax)、达峰浓度(Cmax)、AUC、CL/F和表观分布容积(V/F)分别为10.21±4.13μg/mL,0.37±0.08h-1,1.17±0.23h-1,0.09±0.04h,0.71±0.16h,2.20±0.42h,1.62±0.24h,2.45±0.46μg/mL,12.26±2.21μg·mL-1·h,2.25±0.30L/kg/h,7.41±2.06L/Kg.家兔口服氟苯尼考的生物利用度(F)为(46.83±4.92)%。此结果提示,氟苯尼考的口服生物利用度较低,静脉注射途径能达到较好的治疗效果。
2.比较研究GYP450酶对氟苯尼考在家兔和大鼠上代谢特征的差异15只雄性大鼠,分为氟苯尼考单剂量组、氟伏沙明处理组和酮康唑处理组。氟苯尼考单剂量组动物按100mg/kg体重灌服氟苯尼考；氟伏沙明处理组按60mg/kg体重连续3天灌胃氟伏沙明,一天一次,连续三天,在第三天最后一次给药后30min,动物按100mg/kg体重灌服氟苯尼考；酮康唑处理组的动物与氟伏沙明处理组相同,只是按75mg/kg体重连续3天灌服酮康唑。15只健康的雄性新西兰白兔分为氟苯尼考单剂量组、氟伏沙明处理组和酮康唑处理组。氟苯尼考单剂量组动物灌服25mg/kg体重氟苯尼考；氟伏沙明处理组动物每天按25mg/kg体重灌服氟伏沙明,一天一次,连续3天,在最后一次灌胃氟伏沙明后30min,按25mg/kg体重给家兔灌胃氟苯尼考；酮康唑处理组动物与氟伏沙明处理组相同,按60mg/kg体重连续3天灌服酮康唑。每组动物在氟苯尼考灌服后12h内收集静脉血液,用高效液相色谱测定氟苯尼考的血药浓度变化,3P97药代动力学软件处理药时数据。结果表明：大鼠单剂量口服氟苯尼考的药代动力学分布特征符合一室开放动力学模型。大鼠的CYPIA活性：被氟伏沙明特异性抑制后,血浆中氟苯尼考的Cmax、AUC显著升高(P<0.05),CL/F和V/F显著降低(P<0.05)。大鼠体内的CYP3A活性被酮康唑特异性抑制后,氟苯尼考各个药代动力学参数没有发生显著的变化(P>0.05)。家兔的研究结果表明：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AUC值高达对照组的3倍(P<0.05), CL/F显著降低到原来的1/3(P<0.01)。但是,当体内的CYPIA活,性被氟伏沙明特异性抑制后,血浆中氟苯尼考的各个药代动力学参数均未发生显著变化(P>0.05)。这些结果表明氟苯尼考在不同的动物中是经过不同的CYP450亚型代谢的。CYPIA在大鼠的氟苯尼考代谢中发挥了重要作用,而CYP3A在家兔的氟苯尼考代谢中起主要代谢作用。
3.P-糖蛋白在家兔氟苯尼考口服代谢中的作用用P-糖蛋白的特异性抑制剂维拉帕米研究了P-糖蛋白在家兔氟苯尼考口服代谢中的作用。10只健康的雄性新西兰白兔分为氟苯尼考对照组和维拉帕米处理组。氟苯尼考对照组按25mg/kg体重口服单剂量氟苯尼考。维拉帕米处理组在按9mg/kg体重口服维拉帕米后30min,按25mg/kg体重灌服单剂量的氟苯尼考。用高效液相色谱检测血浆中氟苯尼考的浓度,3P97药代动力学软件处理药时数据。结果表明：氟苯尼考单剂量组动物血浆中氟苯尼考的Ke和T1/2Ke分别为0.37±0.08h-1和2.20±0.42h。维拉帕米特异性抑制了体内的P-糖蛋白后,氟苯尼考的Ke(0.13±0.04h-1)显著降低(P<0.05),T1/2Ke(8.85±2.68h)显著升高(P<0.05),AUC (35.78±5.55μg·mL-1·h)比氟苯尼考单剂量组显著增高了3倍,CL/F(0.75±0.09L/kg/h)是氟苯尼考单剂量组的1/3。这些结果表明：P-糖蛋白在家兔氟苯尼考的口服代谢中发挥了重要作用,抑制P-糖蛋白会导致体内氟苯尼考的生物利用度升高。因此当氟苯尼考与P-糖蛋白的底物、抑制剂或者诱导剂联合用药时,可能会发生药物的相互作用。
4.恩诺沙星对家免氟苯尼考代谢的药代动力学特征的影响。10只新西兰白兔分为氟苯尼考对照组和恩诺沙星处理组。氟苯尼考对照组动物按25mg/kg体重静脉注射单剂量的氟苯尼考；恩诺沙星处理组动物按10mg/kg体重连续静脉注射恩诺沙星3天,在最后一次恩诺沙星给药后15min,动物按25mg/kg体重静脉注射氟苯尼考。在氟苯尼考给药后12h内收集耳缘静脉的血液,用高效液相色谱分析氟苯尼考的药代动力学变化,3P97药代动力学软件处理药时数据。结果表明：恩诺沙星连续处理家兔后,氟苯尼考的药代动力学参数,如AUC、消除半衰期(T1/2β)和内在清除率(CL)等均没有发生显著的变化。这提示临床上家兔按常规剂量连续使用恩诺沙星不会对氟苯尼考的代谢产生药代学影响,恩诺沙星对药物代谢酶的抑制作用可以忽略。
5.氟苯尼考和恩诺沙星对家免肝脏、肾脏和十二指肠的CYP3A6mRNA和CYP3A蛋白表达的影响。12只雄性新西兰白兔分为空白对照组、氟苯尼考处理组和恩诺沙星处理组。空白对照组动物不给予任何药物；氟苯尼考处理组动物按25mg/kg体重灌胃氟苯尼考连续3天。恩诺沙星处理组动物按10mg/kg体重连续灌服恩诺沙星3天,第4天在无菌条件下开胸取出动物的肝脏、肾脏以及十二指肠。提取三种组织的RNA和微粒体蛋白进行RT-PCR和Weatern blot试验。RT-PCR的结果表明,氟苯尼考对家兔CYP3A6的nRNA表达的影响具有组织特异性。连续灌服氟苯尼考能显著的诱导家兔肝脏CYP3A6mRNA的表达(P<0.05),抑制肾脏CYP3A6mRNA的表达(P<0.05),对十二指肠的CYP3A6的表达则没有显著影响(P>0.05)。恩诺沙星能显著的抑制家兔肝脏CYP3A6mRNA的表达(P<0.05),对十二指肠和肾脏的CYP3A6表达没有显著的抑制作用(P>0.05)。Western blot结果显示,氟苯尼考对家兔十二指肠的CYP3A蛋白表达具有显著的诱导作用(P<0.05),但对肾脏和肝脏的CYP3A蛋白表达没有显著作用。恩诺沙星对家兔的肝脏、肾脏和十二指肠的CYP3A蛋白表达均缺乏显著的诱导或抑制作用。
Florfenicol (FFC) is a synthetic broad-spectrum antibiotic in animals. Although it has been widely used in livestock, poultry and carp, the primary enzymes that are involved in the FFC metabolism remains to be defined. Understanding of the metabolism mechanism of FFC is important for avoiding the possible adverse drug-drug interactions and reducing the drug residue in the edible tissues. The aim of the present study was to investigate the metabolism mechanism of FFC and drug-drug interaction. The details are divided into five parts as follows:
To investigate the pharmacological (PK) disposition of FFC, Ten white healthy Newland rabbits were used and randomly allocated into two groups (i.v. or p.o. administration) of five animals each. Aqueous solutions of FFC were administered by i.v. and p.o. route at single doses of25mg/kg b.w. Blood samples were collected in the12h. The plasma concentration of FFC was determined by HPLC system. The pharmacological data analysis was performed by3P97. The results showed that the data of pharmacological parameters were fitted to one-compartment open models follow p.o. and i.v. routes of administration. For the i.v. route, the plasma drug concentration from zero (Co)22.58±5.53μg/mL, elimination rate constant (Ke)0.55±0.07h-1, volume of distribution at steady-state (Vc)1.31±0.21L/kg, half-lives of elimination phase (T1/2Ke)1.33±0.16h, area under curve (AUC)40.06±6.07and apparent body clearance (CLIF)0.68±0.10L/kg/h. For the p.o. route, the intercepts of elimination phases with Y-axis (A)10.21±4.13μg/mL, apparent body clearance (CL/F)0.68±0.10L/kg/h, the elimination rate constant (Ke)0.37±0.08h-1, the absorbtiong rate constant1.17±0.23h-1, lag time0.09±0.04h, half-lives of absorption phase(T1/2Ka)0.71±0.16h, half-lives of elimination phase (T1/2Ke)2.20±0.42h, The maximum plasma concentration (Cmax)2.45±0.46μg/mL, the time of occurrence of Cmax (Tmax)1.62±0.24h, area under curve (AUC)12.26±2.21μg·mL-1·h and apparent distribution of volumn (V/F)7.41±2.06L/kg. The oral bioavailability (F) of FFC was (46.83±4.92)%. Further studies are necessary to identify the range of MIC values for rabbit pathogens and to identify the most appropriate PK-PD parameter needed to predict an effective dose.
Comparatively little is known about the ability of CYP450in the metabolism of FFC with rabbits and rats. Fifteen SD rats were used and divided into three groups in this study. They are FFC alone group, FFC+fluvoxomine-treatment group and FFC+ketoconazole-treatment group, repeactively. For the FFC alone group, FFC was given at a single p.o. dose of100mg/kg.The other two groups were given after p.o. administration of60mg/kg of fluvoxamine and75mg/kg of ketoconazole, respectively, once a day for three days consecutively. On the third day, the animals were given at a single p.o. dose of100mg/kg of FFC30min after the final administration of fluvoxamine or ketoconazole. Fifteen white male New Zealand rabbits were used in this study. The animals were divided into three groups (n=5, each group). For the FFC alone group, FFC was given at the dose of25mg/kg. The other two groups were given after p.o. administration of25mg/kg of fluvoxamine and60mg/kg of ketoconazole, respectively, once a day for three days consecutively. On the third day, the animals were given at a single p.o. dose of25mg/kg of FFC30min after the final administration of fluvoxamine or ketoconazole. The plasma concentration of FFC was analyzed by HPLC system. The mobile phase consisted of a mixture of acetonitrile-water at a ratio of75:25(v/v) and adjusted to pH of2.8with phosphate buffer. The pharmacokinetic analysis of FFC was performed using3P97. The results in rats showed that plasma concentration-time data of FFC was best described by a one-compartment open model. Inhibition of CYP1A activity significant increased the Cmax and AUC of FFC in rats (P<0.05). At the same time, the CLIF and VIF of FFC was significantly decreased compared with FFC Alone group (P<0.05). However, Inhibition of CYP3A activity did not alter the pharmacological disposition of FFC in rats. In rabbits, we found that the deposition of FFC was best described by a one-compartmental open model. We found that inhibition of CYP3A activity significantly increased the AUC and decreased the CLIF of FFC, respectively, but not in the FFC+fluvoxamine group. These suggested that the adverse drug-drug interaction in the use of FFC may occur if the substrates, inducers or inhibitors of CYP3A of the same metabolism mechanism are co-administrated in rabbits. These results suggested that CYP450enzyme play the different role in the metabolism of FFC in the different animals. For the rats, CYP1A was involved in the metabolism of FFC while CYP3A was involved in the metabolism of FFC of rabbits.
To evaluate the role of P-gp in the metablism of FFC, here we employed verapamil (P-gp inhibitor) to investigate the role of P-gp in the PK disposition of FFC. Ten white male New Zealand rabbits (-2kg) were used in this study. The animals were divided into two groups (n=5, each group). For the saline control group, FFC was given at a single p.o. dose of25mg/kg b.w. via nasogastric tube. For the verapamil+FFC group, FFC was administrated as described above,30min after a single p.o. administration of9mg/kg of verapamil. The plasma concentration of FFC was analyzed by HPLC system. The results showed that the deposition of FFC was best described by a one-compartmental open model. We found that inhibition of P-gp significantly increased the AUC and decreased the CL/F of FFC, respectively. Furthermore, a significant decrease of Ke was observed, while an evident increase of T1/2Ke was found. These suggested that the adverse drug-drug interaction in the use of FFC may occur if the substrates, inducers or inhibitors (P-gp or/and CYP3A of the same metabolism mechanism are co-administrated.
To investigat the possible drug-drug interaction between FFC and Enrofloxacin (ENR), ten healthy Newland rabbits weighting～2kg were used and divided to two groups in this study. For the FFC alone group, FFC was given at the intravenous dose of25mg/kg. For the ENR group, the ENR was given at the i.v. dose10mg/kg for three days consecutively. On the third day, the FFC was administrated at the dose of25mg/kg15min after final dose of ENR. Plasma FFC concentration was analysised by HPLC system. The result showed that the PK parameters of FFC, such as A UC, CL and T1/2β, were not changed after administration of ENR in rabbits. This indicated that the inhibitory effect of ENR on disposition of FFC was absent at clinical dosage in vivo in rabbits.
To evaluate the effect of FFC on CYP3A6mRNA and CYP3A protein expression in rabbits, twelve white male New Zealand rabbits were used in this study. The animals were divided into three groups (n=4, each group). For the control group, the animals were not given any drug. For the FFC group, FFC was given at the oral dose of25mg/kg b.w. via nasogastric tube for consecutive three days. For the ENR group, ENR was administrated at the oral dose of10mg/kg for consecutively three days. All the animals were killed2h after the last dose, and the liver, kidney and duodenum were collected immediately. The results of RT-PCR showed that the expression of FFC were specific in the different tissue of rabbits. We found that the expression of CYP3A6mRNA was induced in the liver (P<0.05) while it was inhibited in the kidney of rabbits (P<0.05) for the FFC group, but not in the duodenum (P>0.05). On the other hands, CYP3A6mRNA was inhibited in the liver of rabbits for the ENR group, but not in the kidney or duodenum (.P>0.05). The results of Western blot showed that the expression of CYP3A protein was induced by the FFC in the duodenum(P<0.05), but not in the liver and kidney. CYP3A protein was not induced or inhibited by ENR in the liver, kidney and duodenum(P>0.05). It may be useful in the veterinary clinics when the substrates, inducers or inhibitors of CYP3A enzymes are co-administrated with FFC.
引文
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