恩诺沙星微囊在猪体内的药动学及生物利用度研究

为了比较恩诺沙星微囊和原粉在猪体内的药动学特征及生物利用度,试验采用高效液相色谱法(HPLC),将10头健康猪分2组采用正交试验,经灌胃给药后采血、甲醇提取和HPLC分析,所得药时数据用MCPKP计算机程序处理。恩诺沙星微囊和原粉经口服给药后在猪体内的药时数据均符合一级吸收一室模型,主要药动学参数分别为:t1/2Ka1.73 h±0.93 h和0.36 h±0.31 h(P0.01);Tmax5.69 h±1.68 h和2.04 h±1.06 h(P0.01);t1/2Ke16.53 h±5.23 h和10.17 h±1.87 h(P0.01);Cmax1.71μg/mL±0.47μg/mL和2.51μg/mL±0.45μg/mL(P0.01);AUC为每小时51.98μg/mL±16.08μg/mL和40.58μg/mL±6.40μg/mL;微囊的相对生物利用度为128%。说明恩诺沙星微囊口服给药吸收较慢但完全,达峰时间较长,消除缓慢。     

磺胺间甲氧嘧啶混悬注射液在猪体内的药动学研究

本文比较了磺胺间甲氧嘧啶(SMM)和SMM-Na两种混悬注射液与SMM-Na注射液在猪体内的药物代谢动力学特征,旨在为SMM混悬注射液的开发和注册提供依据。将18头猪随机分成SMM混悬注射液、SMM-Na混悬注射液和SMM-Na注射液3个试验组,按100 mg/kg BW单次肌注给药。HPLC分析血浆中的药物浓度,用MCPKP程序计算动力学参数。3种制剂在猪体内的动力学过程都符合一级吸收二室模型,主要药动学参数如下,SMM混悬注射液:t1/2α(2.86±0.85)h,t1/2β(45.57±8.06)h,AUC(712.04±108.20)mg.L-1.h,Cmax(12.16±0.52)mg/L;SMM-Na混悬注射液:t1/2α(7.90±1.21)h,t1/2β(24.87±12.92)h,AUC(1 489.78±164.63)mg.L-1.h,Cmax(97.86±10.24)mg/L;SMM-Na注射液:t1/2α(0.10±0.04)h,t1/2β(6.20±0.57)h,AUC(1080.83±93.78)mg.L-1.h,Cmax(84.30±4.26)mg/L。SMM混悬注射液虽然消除缓慢,但血药浓度低,有效血药浓度时间短,很难达到临床治疗的要求;SMM-Na混悬注射液血药浓度高,有效血药浓度时间长,是一种较理想的缓释制剂。     

头孢喹肟在猪体内的药动学及生物利用度

10头健康杂种猪,随机交叉设计试验,头孢喹肟按1 mg/kg的剂量分别进行耳缘静脉和颈部肌肉单点注射给药,给药间隔时间为1周.采用反相高效液相色谱法测定血清中头孢喹肟的药物浓度,用药代动力学程序软件3P97处理血清中药物浓度-时间数据.结果表明,静脉注射给药后,猪血清中头孢喹肟的药时数据符合二室开放模型,其主要药动学参数为:t1,2α为0.16 h,t1/2β为1.34 h,V(c)为0.24 L·kg1,cl‘.)为0.26 L·kg-1·h-1,AUC为3.97 mg·L-1·h;颈部肌肉单点注射给药后,猪血清中头孢喹肟的药时数据符合一级吸收二室模型,其主要药动学参数为:t1/2ka为0.08 h,t1/2α为0.84 h,t1/2β日为2.76 h,t(max)为0.32 h,C(max)为1.80 mg·L-1Cl(s)为0.25 L·kg-1·h-1,AUC为4.12 mg·L-1·h,F为102.37%.     

长效土霉素注射液在猪体内的药动学及相对生物利用度研究

对7头健康猪随机交叉设计进行单剂量肌肉注射国产30％长效土霉素注射液和进口20％长效土霉素注射液药动学试验,给药剂量以土霉素计均为20mg／kg体重。用高效液相色谱法测定血药浓度,血药浓度一时间数据用MCPKP计算机程序处理。30％长效土霉素注射液和20％长效土霉素注射液主要药动学参数分别为：吸收半衰期（t1／2ka）为（0．088±0．016）、（0．140±0．076）h;消除半衰期（t1／2β）为（52．499±22．885）、（36．481±21．673）h;达峰时间（Lmax）为（0．609±0．100）、（0．832±0．373）h;峰浓度（Cmax）为（4．956±1．171）、（5．0184-0．948）μg／mL;药时曲线下面积（AUG）为（112．483±18．135）、（109．877±19．949）mg／L·h;以20％长效土霉素注射液为对照物,30％长效土霉素注射液的相对生物利用度（F）为（105．368±26．027）％。结果表明,国产30％长效土霉素注射液与进口20％长效土霉素注射液相比,主要药动学参数无显著差异。此结论为临床合理使用该剂型提供了依据和指导。     

猪体内黏菌素残留检测方法与消除规律

黏菌素抗菌谱广,抗菌作用强,不易产生耐药性,被许多国家和地区批准作为饲料添加剂或兽药在猪、禽、牛和羊等动物上使用。国外黏菌素的残留检测方法主要有微生物法、HPLC、ELISA、薄层色谱法等。HPLC当前的检测限和变异系数均较低,但设备昂贵,且需衍生化,成本高[1];ELISA可作黏菌素的筛选方法[2],但其假阳性较多;薄层色谱法灵敏度不高,主要用于快速检测或对灵敏度要求不高的检测[3]。美国和英国药典规定黏菌素的含量测定使用微生物法,以博代特氏菌作为检测菌,而国内常用《中国药典》规定的以大肠杆菌为检测菌的微生物法[4]。目前我国…     

氟苯尼考混悬剂与常规制剂在猪体内药动学的比较研究

长效制剂能够使药物在动物体内缓慢释放,使有效药物浓度维持较长时间,实现方便给药的目的,同时也克服常规制剂多次给药造成的波峰波谷现象,更好地发挥药效。氟苯尼考混悬剂和常规制剂按20mg/kg体重肌注给药,用高效液相色谱法测定血药浓度。试验所得的血浆浓度-时间数据采用非房室模型统计距原理处理。氟苯尼考混悬剂的主要药动学参数:AUC=44.99μg/(mL.h),MRT=26.62h,t1/2β=16.5h;氟苯尼考常规制剂的主要药动学参数:AUC=54.3μg/(mL.h),MRT=12.97h,t1/2β=11h。试验结果表明氟苯尼考混悬剂在体内吸收缓慢,能够延长药物在体内作用时间。     

赖氨酸磺胺嘧啶的合成及其在猪体内的药动学研究

将磺胺嘧啶钠与赖氨酸在稀酸环境中反应生成水溶性较好的赖氨酸磺胺嘧啶，并作成适宜注射使用的制剂；用赖氨酸啶和磺胺嘧啶钠做药代动力学比较试验，结果表明：在一定条件下，赖氨酸与磺胺嘧啶易结合，赖氨酸磺胺嘧啶的动力学规律较之磺胺嘧啶有较大变化，在猪体内具有一定的长效作用。     

恩诺沙星长效注射液肌注后在猪体内的药动学研究

研究了恩诺沙星长效注射液给猪肌注后的药物动力学特征。将12只白猪随机分成两组,每组6只,分别肌注恩诺沙星注射液(5mg/kg)和长效恩诺沙星注射液(18.75mg/kg),并于给药后0.1, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, 60h, 从前腔静脉采取5ml血,用HPLC分析各血浆样品中的药物浓度,用MCPKP软件计算药动学参数。结果表明:长效恩诺沙星注射液肌注后,经5.64h达到4.86μg/ml的最高浓度,吸收半衰期和消除半衰期分别为2.42h和19.47h,有效浓度维持时间为128.73h, AUC为166.96mg/L.h。吸收半衰期显著延长(p<0.05),达峰时间极显著推迟(p<0.01),消除半衰期也显著长于恩诺沙星注射液。     

猪半体内氟苯尼考对大肠杆菌的药动学-药效学同步关系研究

采用体内药动学和体外药效学联合的方法,研究氟苯尼考在猪半体内抗大肠杆菌的活性,为合理应用氟苯尼考治疗猪大肠杆菌病提供参考.氟苯尼考在MH肉汤及血清中对猪大肠杆菌的最小抑菌浓度(MIC)分别为3.25和8.75 μg·mL-1.猪按20 mg·kg-1的剂量肌内注射氟苯尼考后,药物吸收缓慢且不规则,血浆药物达峰时间为(3.60±1.52)h,峰浓度为(5.28±1.48)μg·mL-1.氟苯尼考在猪体内消除缓慢,体内平均滞留时间为(26.61±9.81)h,消除半衰期为(17.49±8.04)h.半效浓度参数(EC50)为(7.76±4.53)h.AUC0→24h/MIC为(7.69±1.48)h,Cmax/MIC为(0.60±0.17).由于大肠杆菌对氟苯尼考的敏感性较差和氟苯尼考肌内注射药动学特征的限制,应用氟苯尼考,按照常规方案治疗猪大肠杆菌病,可能导致治疗失败.     

两种头孢噻呋注射液在猪体内的比较药动学研究

研究了两种头孢噻呋注射液给猪肌注后的比较药物动力学特征。选用12头健康猪随机分为两组,每组6头,分别肌注上海公谊兽药厂生产的长效盐酸头孢噻呋注射液和美国辉瑞生产的盐酸头孢噻呋注射液（速解灵注射液）,每头5mg／kg。采用超高效液相色谱法测定猪血浆中头孢噻呋的的药物浓度,用Winnonlin5．2药动学分析软件非房室模型处理药时数据,模型200处理肌注给药后的药代动力学参数。结果表明：健康猪肌注两种注射液后,参数MRT、Cmax、tmax统计差异极显著（P〈0．01）,长效盐酸头孢噻呋注射液单剂量肌注给药较速解灵注射液吸收慢,达峰时间显著延迟,达峰浓度显著降低,平均驻留时间显著延长;参数AUC、Kel、t1/2允统计无显著性差异（P〉0．05）,长效盐酸头孢噻呋注射液的相对生物利用度为98．41％,与速解灵注射液的生物利用度相当。本研究可为头孢噻呋注射液的临床合理用药提供参考。     

猪血浆与组织中地西泮的GC-ECD检测方法

本文对地西泮的 GC- ECD检测方法进行了研究。此方法的样品前处理步骤是 :以乙酸乙酯提取 ,经振荡、离心、浓缩后 ,以 C1 8固相萃取 (solid phase extraction,SPE)小柱净化 ,洗脱液以无水硫酸钠脱水后浓缩 ,残存物以色谱纯正己烷溶解 ,GC- ECD检测。色谱条件为 :载气高纯氮流速为 18psi;进样品温度为 2 90℃ ,检测器温度为 375℃ ,补充气氮气流速为 36 m l·min- 1 ;柱温升温程序为 15 0℃保持 0 .5 min,以每分钟 2 0℃的速度升至 2 6 5℃并保持 10 min。本方法线性范围为 2～ 5 0 0 0 ng/ml(或 ng/ g) ,最低检测限以 3倍信噪比计算为 2 ng/ m l(或 ng/ g) ;地西泮在猪血浆、组织中 GC- ECD分析不同浓度样品的平均回收率分别为 :血浆为 88.7% ,肌肉 76 .7% ,肝脏 88.8% ,肾脏 93.1% ,肺脏 89.4 %。本方法批内、批间变异系数的均值分别为 8.89%和 9.6 1% ,方法的重现性较好。本检测方法具有简便、准确、灵敏 ,线性范围宽、适用性强及有机溶剂污染少等特点 ,为地西泮及其他镇静催眠药在动物血浆及组织中的检测工作提供参考     

Bioavailability, pharmacokinetics, and plasma concentration of tetracycline hydrochloride fed to swine

A 2 X 2 crossover design trial was conducted in gilts to determine the bioavailability and pharmacokinetics of tetracycline hydrochloride. The bioavailability of tetracycline hydrochloride administered orally to fasted gilts was approximately 23%. After intravascular administration, the disposition kinetics of tetracycline in plasma were best described by a triexponential equation. The drug had a rapid distribution phase followed by a relatively slow elimination phase, with half-life of 16 hours. Its large volume of distribution (4.5 +/- 1.06 L/kg) suggested that tetracycline is distributed widely in swine tissues. Total body clearance was 0.185 +/- 0.24 L/kg/h. Other pharmacokinetic variables were estimated. In a second trial, 3 gilts were fed a ration containing 0.55 g of tetracycline hydrochloride/kg of feed. Resulting plasma concentration of tetracycline was determined at selected times during 96 hours after exposure to the medicated feed. Plasma drug concentration peaked (0.6 micrograms/ml) at 72 hours after access to the medicated feed.     

Population pharmacokinetics of valnemulin in swine

This study was carried out in 121 pigs to develop a population pharmacokinetic (PPK) model by oral (p.o.) administration of valnemulin at a single dose of 10 mg/kg. Serum biochemistry parameters of each pig were determined prior to drug administration. Three to five blood samples were collected at random time points, but uniformly distributed in the absorption, distribution, and elimination phases of drug disposition. Plasma concentrations of valnemulin were determined by high‐performance liquid chromatography–tandem mass spectrometry (HPLC‐MS/MS). The concentration–time data were fitted to PPK models using nonlinear mixed effect modeling (NONMEM) with G77 FORTRAN compiler. NONMEM runs were executed using Wings for NONMEM. Fixed effects of weight, age, sex as well as biochemistry parameters, which may influence the PK of valnemulin, were investigated. The drug concentration–time data were adequately described by a one‐compartmental model with first‐order absorption. A random effect model of valnemulin revealed a pattern of log‐normal distribution, and it satisfactorily characterized the observed interindividual variability. The distribution of random residual errors, however, suggested an additive model for the initial phase (<12 h) followed by a combined model that consists of both proportional and additive features (≥12 h), so that the intra‐individual variability could be sufficiently characterized. Covariate analysis indicated that body weight had a conspicuous effect on valnemulin clearance (CL/F). The featured population PK values of K_a, V/F and CL/F were 0.292/h, 63.0 L and 41.3 L/h, respectively.     

Diazepam pharmacokinetics after nasal drop and atomized nasal administration in dogs

Musulin, S. E., Mariani, C. L., Papich, M. G. Diazepam pharmacokinetics after nasal drop and atomized nasal administration in dogs. J. vet. Pharmacol. Therap. 34 , 17–24. The standard of care for emergency therapy of seizures in veterinary patients is intravenous (i.v.) administration of benzodiazepines, although rectal administration of diazepam is often recommended for out‐of‐hospital situations, or when i.v. access has not been established. However, both of these routes have potential limitations. This study investigated the pharmacokinetics of diazepam following i.v., intranasal (i.n.) drop and atomized nasal administration in dogs. Six dogs were administered diazepam (0.5 mg/kg) via all three routes following a randomized block design. Plasma samples were collected and concentrations of diazepam and its active metabolites, oxazepam and desmethyldiazepam were quantified with high‐performance liquid chromatography (HPLC). Mean diazepam concentrations >300 ng/mL were reached within 5 min in both i.n. groups. Diazepam was converted into its metabolites within 5 and 10 min, respectively, after i.v. and i.n. administration. The half lives of the metabolites were longer than that of the parent drug after both routes of administration. The bioavailability of diazepam after i.n. drop and atomized nasal administration was 42% and 41%, respectively. These values exceed previously published bioavailability data for rectal administration of diazepam in dogs. This study confirms that i.n. administration of diazepam yields rapid anticonvulsant concentrations of diazepam in the dog before a hepatic first‐pass effect.     

Purification of swine carbonic anhydrase isoenzyme III and measurement of its levels in tissues and plasma

The changes in the levels of carbonic anhydrase isozyme III (CA‐III) in swine plasma and urine have not been previously determined or reported. CA‐III is relatively specific to skeletal muscles, and should therefore be a useful diagnostic marker for muscle diseases. We isolated CA‐III from swine muscle tissues and determined CA‐III levels in the plasma and urine from both healthy and diseased pigs. The levels of CA‐III in the tissues of female swine (age, 3 months) and plasma of young swine (age, 1–5 months) and adult female pigs (age, 2–3 years) were determined using the ELISA system for swine CA‐III. The mean (± SD) levels of CA‐III in the skeletal muscles were 3.8 ± 3.2 mg/g (wet tissue), and in the plasma, 230 ± 193 ng/ml at 1 month, 189 ± 208 ng/ml at 2 months, 141 ± 148 ng/ml at 3 months, 78 ± 142 ng/ml at 4 months and 53 ± 99 ng/ml at 5 months. The mean level of CA‐III in the plasma samples from 2‐ to 3‐year‐old pigs was 18 ± 60 ng/ml. CA‐III in the plasma samples was found to decrease from 1 month until 3 years of age (p < 0.01). We performed far‐western blotting to clarify the cause of the observed decrease in CA‐III in plasma. Our results demonstrated that CA‐III is bound to the transferrin and albumin. In addition, we determined that the levels of CA‐III in plasma and urine samples were higher in diseased swine compared with the healthy pigs.     

Depletion of intramuscularly and subcutaneously injected procaine penicillin G from tissues and plasma of yearling beef steers.

Withdrawal periods required when doses of 24,000 IU and 66,000 IU of procaine penicillin G/kg body weight were administered to yearling beef steers by intramuscular injection daily for five consecutive days were investigated. These dosages are in excess of product label recommendations, but are in the range of procaine penicillin G dosages that have been administered for the treatment of some feedlot bacterial diseases. The approved dose in Canada is 7,500 IU/kg body weight intramuscularly, once daily, with a withdrawal period of five days. Based on the tissue residue data from this study, the appropriate withdrawal period is ten days for the 24,000 IU/kg body weight dose and 21 days for the 66,000 IU/kg body weight dose when administered intramuscularly to yearling beef steers. In a related study, 18 yearling beef steers received 66,000 IU of procaine penicillin G/kg body weight administered by subcutaneous injection, an extra-label treatment in terms of both dose and route of administration, typical of current practice in some circumstances. Deposits of the drug were visible at subcutaneous injection sites up to ten days after injection, with more inflammation and hemorrhage observed than for intramuscular injections of the same dose. These results suggest that procaine penicillin G should not be administered subcutaneously at high doses; and therefore a withdrawal period was not established for subcutaneous injection.     

替米考星微球在猪体内的药代动力学研究

替米考星(tilmicosin,TMS)为动物专用的大环内酯类广谱抗生素,以其优良的抗菌特性[1-2]及特殊的药动学特征[3-4],已广泛应用于畜牧业生产[5-6].但因其对心脏毒性作用大[7],给药途径单一,导致其在兽医临床上推广应用受到极大限制.为了改变替米考星应用现状,拓宽其应用范围,延长其使用寿命,本研究探讨了健康猪肌肉注射TMS-GMS的药物动力学过程并阐明其药动学特征,旨在为临床制定合理的给药方案提供科学依据.     

恩诺沙星纳米混悬注射剂的制备及在猪体内药动学研究

采用高压均质法制备恩诺沙星纳米混悬注射剂并对其制备工艺和质量进行考察、评价;采用高效液相色谱法测定猪血浆中恩诺沙星的浓度,以拜有利注射剂为参照考察恩诺沙星纳米混悬注射剂在猪体内的药动学。结果显示:制备的恩诺沙星纳米混悬注射剂,恩诺沙星的含量为97.9%,平均粒径为(613.21±5.78)nm、PDI(0.22±0.02)、Zeta电位为-2.02mV。恩诺沙星纳米混悬注射剂和拜有利注射剂在猪体内的达峰浓度(Cmax)分别为(0.32±0.12)、(0.67±0.09)mg/L,达峰时间(Tmax)分别为(2.88±0.96)、(0.79±0.26)h,消除半衰期(t1/2ke)分别为(5.99±1.37)、(4.49±1.25)h,AUClast分别为每小时(4.63±1.30)、(4.40±0.45)mg/L,MRTlast分别为(9.59±2.34)、(5.41±1.10)h;与拜有利注射剂相比,恩诺沙星纳米混悬注射剂相对生物利用度为105.2%。结论:高压均质法制备的恩诺沙星纳米混悬注射剂操作简单、不易沉降、再分散性好,理化性质较稳定;与拜有利注射剂相比其Tmax、t1/2k明显增加(P<0.01),MRT显著延长(P<0.01)表明恩诺沙星纳米混悬注射剂具有明显缓释作用且消除缓慢。     

脱氢醋酸钠在猪组织中的残留研究

旨在研究脱氢醋酸钠作为饲料防霉剂应用后在猪组织中的残留消除。选用33只健康杜长大三元杂交猪,200 mg/kg脱氢醋酸钠拌料饲喂1个月。分别于停药1～21 d的不同时间取肌肉、肝脏、肾脏和脂肪组织, HPLC法测定脱氢醋酸钠含量。结果表明,脱氢醋酸钠在猪肾脏和肝脏组织中的残留水平较高,肌肉次之,脂肪中最少。休药1 d时,猪肾脏、肝脏、肌肉和脂肪中的平均残留量分别为1.12 mg/kg、1.06 mg/kg、0.59 mg/kg和0.21 mg/kg;脱氢乙酸钠在组织中的含量低于定量限0.2 mg/kg水平所需要的休药时间分别为:肌肉6 d、肝脏11 d、肾脏13 d、脂肪1 d后。脱氢乙酸钠在猪不同组织中的残留消除半衰期分别为:肌肉6.7 d、肝脏7.2 d、肾脏9.1 d、脂肪5.4 d。上述结果显示,脱氢乙酸钠在猪组织中的残留消除相对较快,组织残留量均低于1.2 mg/kg。     

Ustekinumab pharmacokinetics after subcutaneous administration in swine model

BackgroundDue to multiple similarities in the structure and physiology of human and pig skin, the pig model is extremely useful for biological drug testing after subcutaneous administration. Knowledge of the differences between subcutaneous injection sites could have a significant impact on the absorption phase and pharmacokinetic profiles of biological drugs.ObjectivesThis study aimed to analyze the impact of administration site on pharmacokinetics and selected biochemical and hematological parameters after a single subcutaneous administration of ustekinumab in pigs. Drug concentrations in blood plasma were analyzed by enzyme-linked immunosorbent assay. Pharmacokinetic analyses were performed based on raw data using Phoenix WinNonlin 8.1 software and ThothPro v 4.1.MethodsThe study included 12 healthy, female, large white piglets. Each group received a single dose of ustekinumab given as a 1 mg/kg subcutaneous injection into the internal part of the inguinal fold or the external part of the inguinal fold.ResultsThe differences in absorption rate between the internal and external parts of the inguinal fold were not significant. However, the time of maximal concentration, clearance, area under the curve calculated between zero and mean residence time and mean residence time between groups were substantially different (p > 0.05). The relative bioavailability after administration of ustekinumab into the external part of the inguinal fold was 40.36% lower than after administration of ustekinumab into the internal part of the inguinal fold.ConclusionsHealthy breeding pigs are a relevant model to study the pharmacokinetic profile of subcutaneously administered ustekinumab.