| 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. |
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