2种水温条件下罗非鱼体内氟苯尼考的药物动力学比较

采用药饵给药,药物剂量为10mg·kg^-1,比较研究了22和28℃水温条件下奥尼罗非鱼（Oreochromis niloticus×O．aureus）体内氟苯尼考的药物动力学。结果得出,22℃组和28℃组罗非鱼血浆的峰药浓度（Cmax）分别为4．46和3．90μg·mL^-1,达峰时间（Tmax）均为12h,消除半衰期（T1/2β）分别为10．03和8．12h,药-时曲线下面积（AUC）分别为86．68和72．44h·μg·mL^-1。相应条件下的肌肉Cmax分别为6．88和4．59μg·g^-1,Tmax均为12h,T1／2β分别为10．97和8．03h,AUC分别为112．71和73．66h·μg·g^-1。低温组罗非鱼血浆和肌肉中药物的T1／2β均长于高温组,前者分别比后者长1．91和2．96h,表明低温组罗非鱼体内药物的消除速度慢于高温组。虽然2个水温组血浆和肌肉中药物的Tmax相同,但低温组血浆、肌肉的Cmax和AUC均明显高于高温组,表明低温组罗非鱼吸收利用药物程度高于高温组。     

氟苯尼考在鲟鱼体内的药物代谢动力学研究

采用高效液相色谱检测组织中药物含量,研究水温在(20±1)℃时,杂交鲟经口一次性给予10 mg/kg氟苯尼考后在血液、肌肉、肝脏中的代谢规律.试验结果表明,氟苯尼考经口给药后在鲟鱼血液中的代谢属于一级吸收一室模型,在肌肉和肝脏中属于一级吸收二室模型,且分布广泛,代谢迅速.主要药代动力学参数如下:血液、肌肉、肝脏中的达峰...     

肌注和口灌氟苯尼考在吉富罗非鱼体内的药代动力学

通过肌内注射、口灌两种给药方式,研究氟苯尼考在罗非鱼体内的药物代谢动力学特征。把吉富罗非鱼(GIFT Oreochromis niloticus)随机分成2组,控制水温在30℃,以15 mg/kg分别单剂量肌内注射、口灌给药。经高效液相色谱法(HPLC)测定血浆中氟苯尼考浓度,用Win Nonlin药动学软件分析药动学参数。结果表明:肌内注射氟苯尼考后,药物吸收较慢,消除较快,达峰时间(T_(max))=4 h,峰浓度(C_(max))=4.64μg/mL,消除半衰期(T_(1/2λ)z L)=10.45 h,药-时曲线下面积(AUC)=91.06μg·h/mL。口灌氟苯尼考后,药物吸收较快,消除较慢,T_(max)=1 h,C_(max)=5.92μg/mL,T_(1/2λ)z L=13.13 h,AUC=61.96μg·h/mL。肌内注射、口灌氟苯尼考后,二者的药动学参数差异显著,这一差异表明肌内注射给药吸收相对较慢,但更为完全(肌内注射氟苯尼考的AUC明显较大),消除相对较快。     

氟苯尼考在欧洲鳗鲡体内的药物代谢动力学的研究

应用反相高效液相色谱法对口灌和肌肉注射氟苯尼考在欧洲鳗鲡(Anguilla anguilla)体内的代谢规律进行了研究.按100 mg·kg-1口灌给药后血浆、肌肉、肝脏、肾脏中氟苯尼考浓度的达峰时间分别为2h、6h、0.5h、1h,以后开始缓慢下降,给药2d后血浆、肌肉、肝脏、肾脏中的氟苯尼考浓度分别为4.209μg·mL-1、0.792μg·g-1、0.493μg·g-1、1.448μg·g-1,给药3d后血浆中的氟苯尼考浓度分别为0.0836μg·mL-1,肌肉、肝脏、肾脏中的氟苯尼考浓度均未检出;按100mg·kg-1肌肉注射给药后血浆中氟苯尼考浓度达峰时间为0.5h,以后开始缓慢下降,给药5d后血浆中的氟苯尼考浓度为0.1151μg·mL-1,给药10d后血浆中的氟苯尼考浓度未检出.口灌氟苯尼考在欧洲鳗鲡体内血浆、肌肉、肝脏、肾脏中分布可用开放性二室模型来描述,口灌给药的血浆、肌肉、肝脏、肾脏中的消除半衰期(T1/2β)分别为27.939h、18.844h、11.83h、36.87h;肌肉注射氟苯尼考在欧洲鳗鲡体内血浆、肌肉、肝脏、肾脏中分布可用开放性一室模型来描述,肌肉注射给药的血浆中的消除半衰期(T1/2β)为37.52h.     

丁香酚在罗非鱼体内的药物代谢动力学研究

为了解丁香酚在罗非鱼体内的代谢动力学特征,利用高效液相色谱法(HPLC)检测经丁香酚麻醉后苏醒的吉富罗非鱼(Oreochromis niloticus)血浆、肝脏及肌肉中丁香酚的质量浓度变化。试验结果:采用30 mg/L丁香酚药浴后,罗非鱼血浆、肝和肌肉中的药时数据均符合非房室模型;丁香酚在罗非鱼血浆、肝脏和肌肉中的药代动力学参数显示,峰值浓度(Cmax)分别为8 257.52μg/m L、88.62μg/kg和73.78μg/kg,达峰时间(Tmax)分别为0.5、1和2 h,消除半衰期(t1/2)分别为11.267 3、75.616 1和24.147 4 h,药时曲线下面积(AUC0~∞)分别为83 738.054 3 h·μg/m L、1 466.467 7 h·μg/kg和1 131.101 7 h·μg/kg,0~∞平均滞留时间(MRT0~∞)分别为11.498 2、85.284 4和39.388 7 h,表观分布容积(Vz)分别为1.941 2m L/kg、743.903 0 kg/kg和307.994 9 kg/kg。结果表明,丁香酚在罗非鱼体内分布广泛、消除慢、停留时间长。本研究可为罗非鱼活体运输中麻醉剂的安全使用提供参考。     

水温对氟苯尼考在中华绒螯蟹体内的药物代谢动力学影响

研究不同水温对氟苯尼考在中华绒螯蟹血淋巴、肌肉和肝脏组织中的代谢规律和组织分布的影响.在17℃和28℃水温下,以20 mg/kg剂量单次肌肉注射给药,于给药后不同时间点取各组织样品,氟苯尼考药物含量由高效液相色谱法测定.研究结果表明在两个温度下,血淋巴和肌肉组织中氟苯尼考含量瞬时达到峰值,而肝脏中氟苯尼考含量则随给药时间,呈先上升后下降的趋势.氟苯尼考在中华绒螯蟹体内代谢规律符合二室开放模型,吸收半衰期、消除半衰期、药时曲线下总面积均与温度呈负相关,而总体清除率与温度呈正相关.     

四环素类抗菌药物在吉富罗非鱼体内的代谢动力学研究

给吉富罗非鱼一次灌服50mg/kg剂量的四环素和土霉素浑浊液,研究四环素和土霉素在其肌肉、肝脏和血液中的残留与消除规律。12h后四环素、土霉素在肌肉、肝脏和血液中含量分别达最高,四环素含量分别为0.920mg/kg,2 703mg/kg,1 225μg/mL;土霉素含量分别为0 860,2 188mg/kg和1 075μg/mL。鱼肉中四环素的分布半衰期和消除半衰期分别为8 593,23 50h;土霉素的分布半衰期和消除半衰期分别为8 261,22 979h。216h后,鱼肉中四环素和土霉素均低于0 1mg/kg。     

氟苯尼考在日本囊对虾体内的药代动力学研究

为了给养殖日本囊对虾制定正确的用药方案、确定氟苯尼考的休药期提供科学依据,应用反相高效液相色谱法( RP - HPLC)研究了氟苯尼考在日本囊对虾体内的药物代谢动力学.试验结果表明,在水温23±0.5℃,盐度29.91的条件下,氟苯尼考在肝脏、肌肉和血淋巴的平均回收率为93.37％、91.79％、91.82％;试验数据经药代动力学软件3p97分析表明,日本囊对虾采用氟苯尼考单次腹部肌肉注射,其肌肉药一时数据符合二室模型,肝脏和血淋巴药一时数据符合一室模型.其中,氟苯尼考在肝脏、肌肉和血淋巴中的主要动力学参数分别为:浓度一时间曲线的曲线下面积AUC分别为10.31、50.77、14.33(μg/g)·h;药物的峰值浓度C(max)分别为13.03、10.46、8.031 μg/g;药物浓度处于峰值时的时间Tp分别为0.2044、0.2298、0.6544 h;吸收半衰期分别为0.6771、0.4746、0.4193 h;消除半衰期分别为3.766、16.16、4.917 h.建议在23 ±0.5℃的水温条件下,氟苯尼考对日本囊对虾的休药期不少于7d.     

氟苯尼考的药效学及其在水产动物中的代谢动力学研究进展

氟苯尼考具有很强的抗菌活性,对大多数革兰氏阳性菌及阴性菌都有作用,在水产养殖上有广泛应用。本文综述了氟苯尼考在水产动物中的药效学、药物动力学及残留消除规律的研究进展,以期为氟苯尼考在水产病害防治中的科学性和规范性应用提供思路,促进我国水产品的安全与水产养殖的可持续发展。     

氟苯尼考及氟苯尼考胺在鲤体内的残留

在水温(18±1)℃下,采用高效液相色谱串联质谱法研究了氟苯尼考及其主要代谢物氟苯尼考胺在体质量(100±10)g鲤(Cyprinus carpio)体内的代谢及残留规律,以制定休药期。实验鱼间隔24h按15 mg.kg-1体质量的剂量口灌给药,连续给药3次,在给药后0.5h、1 h、2h、4h、8h、12h、24h、2d、3d、5d、7d、10d、15d、20d检测肌肉、皮肤内氟苯尼考和氟苯尼考胺的含量。结果表明:氟苯尼考在鲤体内的代谢速度快,2~4 h出现峰值;肌肉中氟苯尼考和氟苯尼考胺的残留浓度高于皮肤,肌肉和皮肤中氟苯尼考的含量均高于氟苯尼考胺,皮肤中的代谢速度较快。按欧盟标准相应的休药期不少于2d,按日本标准则不少于10 d。     

罗非鱼体内氟甲砜霉素的高效液相色谱测定方法研究

建立了罗非鱼(Oreochromis niloticus×O.aureus)血浆、肌肉和肝脏内氟甲砜霉素的高效液相色谱测定方法(HPLC法)。采用内标法和峰高法定量,方法准确,重复性好,灵敏度较高。8、1和0.125μg·mL-13个浓度水平的加标回收率为89.16%-96.13%;对应的批内精密度和批间精密度分别为2.21%-6.55%和2.11%- 7.71%。方法检出限为0.03μg·mL-1。结果表明,此方法非常适合用于罗非鱼体内氟甲砜霉素的动力学和残留研究。     

Efficacy of florfenicol for control of mortality associated with Francisella noatunensis subsp. orientalis in Nile tilapia,Oreochromis niloticus (L.)

Francisella noatunensis subsp. orientalis (Fno) (syn. F. asiatica) is an emergent Gram‐negative facultative intracellular bacterium. Although it is considered one of the most pathogenic bacteria in fish, there are no commercially available treatments or vaccines. The objective of this project was to determine the most efficacious concentration of florfenicol (FFC) [10, 15 or 20 mg FFC kg^?1 body weight (bw) per days for 10 days] administered in feed to control experimentally induced infections of Fno in Nile tilapia, Oreochromis niloticus (L.), reared in a recirculating aquaculture system. The cumulative mortality of fish that received 0, 10, 15 or 20 mg FFC kg^?1 bw per day was 60, 37, 14 and 16%, respectively. Francisella noatunensis subsp. orientalis genome equivalents were detected in water from all challenged groups with slight reduction in the concentration in the florfenicol‐treated groups 4 days after treatment. The mean LOG of CFU Fno mg^?1 spleen was 3–5 and was present in all challenged groups at necropsy 11 days after treatment (21 days after challenge). Results show that florfenicol administered at doses of 15 and 20 mg FFC kg^?1 bw per days for 10 days significantly reduced mortality associated with francisellosis in Nile tilapia.     

Pharmacokinetics of florfenicol and behaviour of its metabolite florfenicol amine in orange‐spotted grouper (Epinephelus coioides) after oral administration

Pharmacokinetics and elimination of florfenicol and florfenicol amine in grouper held in sea water at 23.3 ± 0.8 °C were studied using HPLC method after they were given a single peroral dose of florfenicol at 24 mg kg^?1 body weight. Florfenicol was rapidly absorbed from intestine and distributed extensively to all the tissues examined. The maximum concentrations (C_max, μg g^?1 or μg mL^?1) in plasma and tissues were observed at 2–6 h (the time to reach maximum concentration, T_max) except for bile (T_max = 24 h) and were in the order of intestine (52.02 ± 25.07) > bile (49.41 ± 28.16) > gill (45.12 ± 11.10) > plasma (28.28 ± 5.43) > liver (21.97 ± 12.08) > muscle (21.63 ± 6.12) > kidney (20.88 ± 11.28) > skin (19.10 ± 5.88). The drug distribution level was higher in plasma than in extravascular tissues except for bile, based on the ratios of the area under concentration–time curve between tissue and plasma (AUC_{tissue/plasma}). The elimination of florfenicol was rapid in fish, and the corresponding half‐lives (T_1/2β) in the order of magnitude were bile (13.92 h) > muscle or liver (12.31 h) > skin (11.77 h) > plasma (11.57) > gill (11.04 h) > intestine (10.55 h) > kidney (10.05 h). The delayed T_max, lower C_max and longer T_1/2β for florfenicol amine compared with florfenicol were measured in grouper.     

Depletion of florfenicol amine in tilapia (Oreochromis sp.) maintained in a recirculating aquaculture system following Aquaflor®‐medicated feed therapy

Aquaflor^® [50% w w^?1 florfenicol (FFC)], is approved for use in freshwater‐reared warmwater finfish which include tilapia Oreochromis spp. in the United States to control mortality from Streptococcus iniae. The depletion of florfenicol amine (FFA), the marker residue of FFC, was evaluated after feeding FFC‐medicated feed to deliver a nominal 20 mg FFC kg^?1 BW d^?1 dose (1.33× the label use of 15 mg FFC kg^?1 BW d^?1) to Nile tilapia O. niloticus and hybrid tilapia O. niloticus × O. aureus held in a recirculating aquaculture system (RAS) at production‐scale holding densities. Florfenicol amine concentrations were determined in fillets taken from 10 fish before dosing and from 20 fish at nine time points after dosing (from 1 to 240 h post‐dosing). Water samples were assayed for FFC before, during and after the dosing period. Parameters monitored included daily feed consumption and biofilter function (levels of ammonia, nitrite and nitrate). Mean fillet FFA concentration decreased from 13.77 μg g^?1 at 1‐h post dosing to 0.39 μg g^?1 at 240‐h post dosing. Water FFC concentration decreased from a maximum of 1400 ng mL^?1 at 1 day post‐dosing to 847 ng mL^?1 at 240 h post‐dosing. There were no adverse effects noted on fish, feed consumption or biofilter function associated with FFC‐medicated feed administration to tilapia.     

Pharmacokinetic–pharmacodynamic modelling for the determination of optimal dosing regimen of florfenicol in Nile tilapia (Oreochromis niloticus) at different water temperatures and antimicrobial susceptibility levels

Optimized dosing regimen is key to the effective use of antibacterials and to minimizing drug‐related side effects. The current study established a pharmacokinetic–pharmacodynamic (PK‐PD) model for the determination of optimal antibacterial dosing regimen in fish taken into consideration the temperature‐dependent PK and the pathogen‐dependent antimicrobial susceptibility, using florfenicol (FF) in Nile tilapia as an example. The calculated optimal dosages significantly varied by temperature and target MIC levels, ranging from 2.23 (MIC 1 µg/ml at 24°C) to 34.88 mg kg^?1 day^?1 (MIC 4 µg/ml at 32°C). The appropriateness of the calculated dosages was successfully verified by the in vivo studies. After 5 days of oral administration of the calculated optimal dosage at 24°C, the predicted plasma drug values were in line with the mean observed C_min(ss) while at 28 and 32°C underestimation of the C_min(ss) in a dose‐dependent manner was observed and likely due to the occurrence of non‐linear PK at high dosages. The averaged serum protein binding of FF was 19.1%. Our results demonstrated the appropriateness and clinical applicability of the developed PK‐PD approach for the determination of optimal dosing regimens at given temperatures and MICs. Saturation metabolism and PK non‐linearity of FF in tilapia warrant further study.     

氟苯尼考用于水产养殖的安全性

氟苯尼考(florfenicol)，又称氟甲砜霉素，是一种新型广谱高效抗菌药物，自20世纪90年代初开始应用于水产养殖。1990年氟苯尼考首次在日本上市用于治疗黄尾蛳(Seriola lalandei)、真鲷(Pagrosomus major)、银大马哈鱼(Oncorhynchus kisutch)、日本竹笑鱼(Trachurus japonicus)、虹鳟(Oncorhynchus mykiss)、香鱼(Plecoglossus altivelis)、罗非鱼和鳗鱼等的假结核性巴氏杆菌病(pasteurellosis)和链球菌病(streptococcosis)，随后，韩国、挪威、智利、加拿大、英国等分别上市用于治疗专门疾病。中国1999年批准氟苯考尼为国家二类新兽药，在水产养殖上可用于治疗鳗鲡爱德华氏病和赤鳍病。本研究从氟苯尼考抗菌活性与药效学、药代动力学、毒理学、以及药物残留、耐药性等方面探讨其用于水产养殖病害防治的安全性，旨为该药在中国水产养殖中的科学合理应用提供理论参考。     

Pharmacokinetics,optimal dosages and withdrawal time of florfenicol in Asian seabass (Lates calcarifer) after oral administration via medicated feed

Asian seabass (Lates calcarifer) is an economically important fish in Asian and Australian markets, but few pharmacokinetic (PK) data of antimicrobial drugs in this species is available. The present study investigated the PK behaviour of florfenicol (FF) through medicated feed in Asian seabass cultured at 25°C. The serum and muscle/skin concentrations of FF and its metabolite florfenicol amine (FFA) were determined by the HPLC-FLD method and analysed by one-compartmental model. The optimal dosages were determined by pharmacokinetic-pharmacodynamic (PK-PD) approach and the linear regression analysis was used to determine the withdrawal time (WDT). The PK study following a single oral administration of 15 mg/kg FF via medicated feed revealed that the absorption half-life (t_1/2Ka), elimination half-life (t_1/2K), peak concentration (C_max), area under the concentration-time curve (AUC), volume of distribution (Vd/F) and clearance (CL/F) were 1.47 h, 8.07 h, 8.61 μg/ml, 146.41 h·μg/ml, 1.19 L/kg and 0.102 L/kg/h, respectively. The muscle/skin concentration-time profile was similar to that of the serum, suggesting well distribution but only a small fraction of FF was metabolized to FFA. The optimal dosage for a minimum inhibitory concentration of 2 μg/ml was calculated as 13.38 mg/kg/day. The appropriate WDT after multiple oral medications with 15 mg/kg FF once daily for 7 days was determined as 8 days. Information obtained from the current study can potentially be applied for the treatment of bacterial diseases in farming Asian seabass.     

盐酸土霉素在奥尼罗非鱼体内的药代动力学及残留研究

在水温(25±2)℃条件下,以15 mg/kg鱼体重的剂量给奥尼罗非鱼单次口灌盐酸土霉素,采用高效液相色谱法测定血浆和肌肉组织中的药物浓度,研究盐酸土霉素在奥尼罗非鱼体内的代谢及消除规律。结果显示:血药时间数据符合一级吸收二室开放模型,半衰期(T1/2Ka、T1/2α、T1/2β)分别为4.79、4.10、45.20 h,最大血药浓度为1.50μg/m L,达峰时间为7.30 h,药时曲线下面积(AUC)为42.35μg·h/m L。肌肉作为可食性组织,选取肌肉组织作为残留检测的靶组织,以0.1 mg/kg为最高残留限量,在本试验条件下,建议休药期不低于10 d。