伊维菌素药动学研究进展

综述了伊维菌素在动物体内的吸收、分布、代谢、排泄过程以及其药代动力学研究进展,以期为伊维菌素的临床用药和新兽药开发提供依据。     

伊维菌素微球在家兔体内的药动学

皮下注射伊维菌素 (IVM )微球悬液 (5 0mg/kg及 10 0mg/kg)和害获灭 (1%伊维菌素 ,0 5mg/kg) ,RP HPLC UV法定量 ,研究了IVM在家兔体内的药物动力学。害获灭皮下注射给药 ,药 时数据符合一级吸收一室开放模型 ,主要动力学参数为 :t1/2ka=7 2 4± 2 96h ;t1/2ke=36 38± 8 6 6h ;tmax=2 1 4 6± 4 82h ;Cmax=2 2 53± 2 32ng/ml;AUC =174 9± 318ng/1.h ,其动力学参数表现比较明显的个体差异 ,且与其它动物有明显差别。微球皮下注射一周后 ,血药浓度呈较稳定状态 ,到第 4 2天 (高剂量组 )和第 32天 (低剂量组 ) ,血浆中测不出H2 B1a(低于 2 5ng/ml)。以房室模型拟合 ,微球高低剂量组均符合有吸收二室开放模型 ,主要药动学参数均表现显著的个体差异。     

一种兽用阿苯达唑伊维菌素粉的制备及稳定性研究

以阿苯达唑、伊维菌素为主原料,十二烷基硫酸钠为润湿剂,倍他环糊精、聚乙二醇6000为助溶剂,主原料与辅料经过混合、研磨粉碎制得阿苯达唑伊维菌素粉。配方组合为质量比M（阿苯达唑）:M（伊维菌素）:M（十二烷基硫酸钠）:M（倍他环糊精）:聚乙二醇6000=10:0.2:8:20:61.8。考察制得的阿苯达唑伊维菌素粉水中分散性良好,符合干混悬剂的沉降体积比要求,按阿苯达唑伊维菌素粉的质量标准检测为合格,低含量的伊维菌素含量均匀度符合要求,可以实现难溶性药物阿苯达唑的拌料和饮水给药。密闭保存,长期试验24个月,性状、外观几乎无改变;干燥失重由2.4%升高至2.6%;阿苯达唑含量由99.2%下降至97.3%;伊维菌素含量由100.2%下降至97.0%,含量下降不超过药物标示量百分含量的10%,符合规定。该阿苯达唑伊维菌素粉配方组成合理,工艺简单科学、操作简便,产品质量合格且稳定,有效期暂定为2年。     

复方伊维菌素乳液在山羊体内的药代动力学研究

为了探讨复方伊维菌素乳液在动物体内的药物代谢,为兽医临床提供用药参考。试验选取7只山羊,每只山羊按0.1 mL/kg (伊维菌素0.2 mg/kg, 阿苯达唑10 mg/kg)剂量口服,给药后0.5、1、2、3、4、6、8、12、16、24、36、48、60 h颈静脉采血5 mL,分离血清,-20 ℃保存,用高效液相色谱仪检测样品血药浓度。试验结果表明,①伊维菌素在山羊体内的代谢情况为：0.5 h,0.112151 μg/mL; 第1次达峰时间为4 h, 0.302702 μg/mL;第2次达峰时间为16 h,0.258284 μg/mL;60 h,0.011118 μg/mL。②阿苯达唑在山羊体内的代谢情况为：0.5 h, 0.049285 μg/mL;第1次达峰时间为8 h,4.95283 μg/mL ;第2次达峰时间为16 h,5.694551 μg/mL;60 h,0.06434 μg/mL。复方伊维菌素中的伊维菌素和阿苯达唑在山羊体内代谢时间短,第60小时已达到很低的血药浓度。     

盐酸阿苯达唑亚砜的合成

以阿苯达唑为原料,采用一锅合成法,通过氧化、酸化反应得到目标产物盐酸阿苯达唑亚砜。以丙酮为反应溶剂,当阿苯达唑和盐酸的投料比为30 g∶13 mL,阿苯达唑和双氧水的投料比为1∶1.01(n∶n),反应时间为30 min时,制备的盐酸阿苯达唑亚砜的收率为95.78%,通过IR、1H-NMR1、3C-NMR和ESI-MS分析对其产物结构进行了确证。     

阿苯达唑纳米混悬剂的研制及其评价

为了解决阿苯达唑的溶解性和口服吸收难题,借助高分子活性剂的稳定作用,利用反溶剂法-高压匀质法制备阿苯达唑纳米混悬剂,并考察该制剂的药学特征及稳定性;研究该制剂在大鼠体内的药代动力学。研究创制的纳米混悬液在电镜下药物形状大小均一,中位粒径为358.1nm。其药学特征符合《兽药质量标准》（2017版）中对混悬液的质量要求。6个月加速试验表明,该制剂外观色泽、含量、pH值、沉降体积比、重分散性均未发生明显变化,且放置6个月后粒径没有显著变化。该阿苯达唑纳米混悬液的Cmax为5.895μg/mL,显著高于参比制剂阿苯达唑伊维菌素粉、佛山正典阿苯达唑混悬液的2.804和2.053μg/mL。与阿苯达唑伊维菌素粉、佛山正典阿苯达唑混悬液相比,该制剂的相对生物利用度分别为214% 和299.74% ,表明该阿苯达唑纳米混悬液能显著提高阿苯达唑的吸收,将有助于提高临床治疗效果。     

牛肉中阿苯达唑及其代谢产物残留的检测

阿苯达唑是一种广谱抗蠕虫药,但是由于用药不当等原因,其在动物可食性组织中的残留可能刺激神经系统及消化系统、触发过敏反应甚至出现肝功能异常。本试验基于5μg/kg的检验限建立牛肉中的阿苯达唑及其代谢产物的检测方法——高效液相色谱法。样品中残留的阿苯达唑及其主要代谢产物阿苯达唑砜和阿苯达唑亚砜,经乙醚提取,乙腈和己烷萃取,由高效液相色谱（配紫外检测器）测定得到阿苯达唑及其亚砜与砜的平均回收率分别为71.8%～88.6%、78.1%～85.6%和83.1%～91.9%,变异系数分别为2.8%～9.2%、0.9%～4.9%和1.4%～4.8%。     

伊维菌素在樱桃谷鸭体内证治药物动力学研究

本试验利用证治药动学的方法,研究了伊维菌素在樱桃谷鸭体内药物动力学变化,旨在验证黄曲霉毒素B1中毒后中药制剂＂保肝护肾脱霉素＂的药理作用。将117只健康1日龄的樱桃谷鸭随机平均分成3组,Ⅰ组（正常组）饲喂健康饲料,饲喂28d。Ⅱ组（病理组）前7d饲喂健康饲料,8-21d饲喂含有黄曲霉毒素B1的霉变饲料,22-28d饲喂健康饲料。Ⅲ组（中药反证组）前7d饲喂健康饲料,8-22d饲喂含黄曲霉毒素B1的霉变饲料,22-28d饲喂健康饲料,与此同时对每只鸭子每天口服保肝护肾脱毒素液5mL,口服7d,第29天,给上述3组试验鸭口服伊维菌素溶液,分别在给药前（0h）和给药后时间点从鸭的颈静脉采血,采用高效液相荧光色谱法进行检测。结果显示,黄曲霉毒素B1造成的病理损伤,能改变伊维菌素内服在鸭体内的药动学特征,表现出吸收减慢,吸收程度减弱,消除速率减弱的药动学特征。经过中药制剂＂保肝护肾脱霉素＂反证后,伊维菌素的吸收及消除速度都有不同程度地增加。试验结果表明,从药动学角度说明中药制剂＂保肝护肾脱霉素＂对黄曲霉毒素B1造成的病理损伤有修复作用。     

阿苯达唑散驱鸡线虫的临床试验

阿苯达唑散驱鸡线虫的临床疗效试验结果表明,对自然感染蛔虫的75日龄鸡,用阿苯达唑散10、20、40mg/kg体重,一次量拌料内服,对鸡线虫的精计、粗计驱虫率和驱净率均为100%。推荐剂量10~20mg/kg体重,使用安全方便。     

Enhanced Plasma Availability of the Metabolites of Albendazole in Fasted Adult Sheep

Lifschitz, A., Virkel G., Mastromarino, M. and Lanusse C., 1997. Enhanced plasma availability of the metabolites of albendazole in fasted adult sheep. Veterinary Research Communications, 21 (3), 201-211The influence of fasting prior to treatment and of dosing rate on the plasma availability and disposition kinetics of albendazole (ABZ) and its sulphoxide (ABZSO) and sulphone (ABZSO2) metabolites was studied in adult sheep grazing on pasture. A micronized suspension of ABZ was administered orally at either 7.5 mg/kg (group A) or 11.3 mg/kg (group C) to sheep fed ad libitum, and at 7.5 mg/kg to sheep subjected to a 24 h fasting period prior to treatment (group B). Blood samples were taken serially over 96 h after treatment, and the plasma was analysed for ABZ and its metabolites by high-performance liquid chromatography. ABZSO and ABZSO2 were recovered from the plasma. Fasting induced marked modifications in the pharmacokinetic behaviour of the ABZ metabolites in sheep. An extended absorption process, with a delayed peak concentration in the plasma, was observed for both metabolites in the fasted sheep. Significantly higher area under the curve (AUC) and peak plasma concentration (Cmax) values were obtained for both metabolites in the fasted animals compared to those fed ad libitum. Delayed elimination with prolonged detection in plasma was also observed in the fasted sheep. Treatment with ABZ at 7.5 mg/kg in the starved animals resulted in bioequivalence to the administration of the compound at a 50% higher dose rate (11.3 mg/kg) in the fed animals. It is suggested that fasting enhances ABZ dissolution and absorption by delaying its passage down the digestive tract.     

丙硫咪唑在鸡体内的药代动力学及组织残留的研究

给鸡单剂量口服丙硫咪唑(15mg/kg),用HPLC法测定不同时间的鸡体内药物及其代谢物的浓度.结果,在血浆和组织中均未发现丙硫咪唑,而其两个代谢物丙硫咪唑亚砜(亚砜)和丙硫咪唑砜(砜)在血浆中的药代动力学行为符合方程:C(亚砜)=22.3581(e~(-0.142(t-0.6053))-e~(-0.4505(t-0.8053)));C(砜)=4951.7774(e~(-0.2769(t-0.9111))-e~(0.278(t-0.9111)))。亚砜和砜的主要药动学参数分别为:消除相半衰期(t1/2ke)为4.87和2.57h,表观分布容积(Vd)为0.98和0.76L/kg,峰时间(Tm)为4.34和4.52h,峰浓度(Cm)为8.98和7.22μg/mL。亚砜在心、肝、胰、肺、肾等组织中的残留量:给药后3d分别为1.14、5.35、2.42、1.78、2.45μg/g;5d分别为0.281.79、2.34、1.13、1.16μg/g;7d分别为0.12、0.68、1.69、0.48、0.69μg/g.砜在上述组织中的残留量:给药后3d分别为3.15、10.44、8.16、0.99、2.83μg/g;5d分别为1.53、1.04、4.11、0.86、0 89μg/g;7d分别为:0.77、0.67、2.09、0.53、0.12μg/g。     

丙硫苯咪唑在猪体内的药代动力学研究

本文建立了用反相高效液相色谱法测定丙硫苯咪唑及其代谢物丙硫苯咪唑亚砜、丙硫苯咪唑砜的血药浓度的方法,并测定了6头健康猪口服丙硫苯咪唑(25mg/kg)后亚砜和砜的血药浓度及有关药代动力学参数。结果:给药后20min采血,6头猪血中,丙硫苯咪唑原形药均未检出,而以丙硫苯咪唑亚砜和丙硫苯咪唑砜的形式出现。以NaVa pack C18 4μm 0.39×15cm为固定相,紫外检测器波长为290nm,甲苯咪唑为内标物,测定丙硫苯咪唑亚砜和砜.本法测得血清中亚砜的最低含量为23.56ng/mL,砜为16.54ng/mL。亚砜平均回收率为93.73±6.75％,砜为90.044±5.33％,不同浓度水平测定结果的日内和日间变动系数均在10％以下。丙硫苯咪唑亚砜和砜的药代动力学符合有吸收因素二室模型,健康猪口服丙硫苯咪唑后,亚砜半衰期(t1/B)为12.6466±1.8491h;血浆清除率(CL_B)为0.1364±0.0921L/(kg·h);血药浓度达峰时间(Tmax)为10h,峰浓度(Cmax)为11.919±1.382μg/mL血清;药时曲线下面积(AUC)为1156.69±742.52μg/(mL·h)。     

Ivermectin in Senegalese Peulh Sheep: Influence of Sex on Plasma Disposition

The plasma disposition kinetics of ivermectin following a single subcutaneous administration of 0.2 mg/kg was investigated in male and female Senegalese Peulh sheep. Ten clinically healthy animals (5 males and 5 females) weighing 38–45 kg were used in this trial. Blood samples were collected by jugular puncture at different times between 0.5 h and 30 days post treatment. After plasma extraction and derivatization, samples were analysed by HPLC with fluorescence detection. Computerized kinetic analysis was carried out and mean parameters were statistically compared with the Mann–Whitney U-test. The area under the concentration–time curve (AUC) was significantly higher (p < 0.0027) in females than in males. Although the differences in maximum concentration (C _max), mean residence time (MRT) and half-life of elimination (t _1/2el) between males and females did not achieve statistical significance, values tended to be higher in females. Sex differences may be parallel with the level of storage in fat. Further investigations are required to improve the use of ivermectin in Senegalese sheep and findings may be used to predict optimal anthelmintic strategies for management of African species depending on the parasites present in a production system.     

Influence of Diet Type and Pretreatment Fasting on the Disposition Kinetics of Albendazole in Sheep

The influence of the quality and quantity of diets on the disposition kinetics of albendazole were studied in sheep in two different experiments. The plasma concentration profiles of albendazole sulphoxide and albendazole sulphone were measured following intraruminal administration of albendazole at 5.0 mg/kg body weight in weaner sheep offered three different diets: 100% green Sorghum spp., 100% dry mature Cenchrus ciliaris hay and a 50:50 mix of these two diets. The peak plasma concentrations and the availability of the albendazole metabolites, as measured by the area under the concentration–time curve, were significantly higher (p<0.01) in the animals offered exclusively dry fodder compared to other diets. Changing the diet from dry to green fodder resulted in a significantly lower systemic availability of the drug metabolites. It is suggested that a decreased transit time of the digesta in the bowel on the green diet, with its high water content, limited the systemic availability of the drug by reducing the time available for gastrointestinal absorption.An experiment on the influence of different levels of pretreatment fasting on the pharmacokinetics of albendazole revealed significantly higher (p<0.05) plasma concentrations of the anthelmintically active sulphoxide metabolite from 12 h onwards following administration of the drug in animals subjected to 24 h of pretreatment fasting compared to other groups with pretreatment fasting of 8, 12 or 18 h. The area under the concentration–time curve and the minimum residence time of the drug metabolites were significantly greater (p<0.05) in animals that had been fasted for 24 h. It is suggested that fasting induces a decrease in the flow of digesta through the gastrointestinal tract of ruminants and prolongs the duration of dissolution of the drug, resulting in enhancement of the absorption of albendazole and of the systemic availability of its metabolites.     

Comparative Disposition Kinetics of Albendazole in Sheep Following Oral and Intraruminal Administration

The pharmacokinetics of albendazole was studied in sheep following single oral and intraruminal administration at nematocidal dose rates. The disposition curves of its metabolites indicated increased uptake of the drug in sheep following intraruminal as compared to oral dosing (p<0.05). The increased bioavailability of benzimidazole anthelmintics given by the intraruminal route could be exploited for optimizing the use of anthelmintic for sustained parasite control in small ruminants.     

Aspects of the Pharmacokinetics of Albendazole Sulphoxide in Sheep

The plasma disposition kinetics of albendazole sulphoxide (ABZSO), ((+)ABZSO and (–)ABZSO) and its sulphone metabolite (ABZSO₂) were investigated in adult sheep. Six Corriedale sheep received albendazole sulphoxide by intravenous injection at 5 mg/kg live weight. Jugular blood samples were taken serially for 72 h and the plasma was analysed by high-performance liquid chromatography (HPLC) for albendazole (ABZ), ABZ sulphoxide (ABZSO) and albendazole sulphone (ABZSO₂). Albendazole was not detected in the plasma at any time after the treatment, ABZSO and ABZSO₂ being the main metabolites detected between 10 min and 48 h after treatment. A biexponential plasma concentration versus time curve was observed for both ABZSO and ABZSO₂ following the intravenous treatment. The plasma AUC values for ABZSO and ABZSO₂ were 52.0 and 10.8 (g.h)/ml, respectively. The ABZSO₂ metabolite was measurable in plasma between 10 min and 48 h after administration of ABZSO, reaching a peak concentration of 0.38 g/ml at 7.7 h after treatment. Using a chiral phase-based HPLC method, a biexponential plasma concentration versus time curve was observed for both ABZSO enantiomers. The total body clearance was higher for the (–) than for the (+) enantiomer, the values being 270.6 and 147.75 (ml/h)/kg, respectively. The elimination half-life of the (–) enantiomer was shorter than that of the (+) enantiomer, the values being 4.31 and 8.33 h, respectively. The enantiomeric ratio (+)ABZSO/(–)ABZSO at t ₀ was close to unity. However, the ratio in the plasma increased with time.     

A Survey of Anthelmintic Resistance by Nematodes on Three Sheep and Two Goat Farms in Hisar (India)

Singh, S. and Yadav, C.L., 1997. A survey of anthelmintic resistance by nematodes on three sheep and two goat farms in Hisar (India). Veterinary Research Communications, 21 (6), 447-451     

高山美利奴羊在低海拔地区适应性研究

为研究高山美利奴羊在低海拔地区的适应情况,选择100只断奶母羊,分成主产区(高山寒旱草原生态区)和推广区(低海拔地区)2组,测定周岁和成年羊的体重、羊毛纤维直径和血液生化指标.结果表明:推广区高山美利奴羊体重均显著高于同年龄主产区羊(P<0.05);推广区成年羊的羊毛纤维直径显著高于主产区成年羊(P<0.05),但推广...