氟氯苯菊酯在犬体内的药动学初步研究

研究自制1%氟氯苯菊酯浇泼剂在健康家犬体内的药代动力学特征。选用6条健康犬,以2mg/kg单剂量沿背中线浇泼,采用反相高效液相色谱法(RP-HPLC)测定犬血浆中氟氯苯菊酯浓度,用3P97药动软件处理药时数据,计算药代动力学参数。氟氯苯菊酯的药时数据符合一级吸收二室开放模型,主要药动学参数为:T1/2α为(3.622±1.079)h,T1/2β为(22.654±0.417)h,T1/2Ka为(1.684±0.240)h,AUC为(47.385±1.709)μg.mL-1.h,Tpeak为(4.165±0.187)h,Cmax为(1.902±0.064)μg/mL,Lagtime为(0.489±0.002)h。健康家犬单次给予氟氯苯菊酯浇泼剂后,吸收、消除均缓慢,药物在动物体内作用时间较长。     

猪肌肉注射多拉菌素的药物动力学研究

对多拉菌素在猪体内的肌肉注射药物动力学进行了研究。长白×杜洛克杂交猪5头,临床健康,体重36kg~50kg。以300μg/kg体重剂量通过肌肉注射给药,血浆样品经乙腈处理后过18C富集柱,用甲醇提取多拉菌素并进行衍生化反应,以反向HPLC测定血清中的药物浓度,药物动力学参数用MCPKP程序进行处理。结果表明,猪肌肉注射多拉菌素后,血浆药物浓度可测至25d,药物浓度-时间曲线符合二室开放模型。主要药物动力学参数为,t1/2α0.056d±0.022d,t1/2β3.20d±1.34d,AUC223.51μg/(L.d)±65.20μg/(L.d),CMAX28.99μg/L±10.69μg/L,Tp1.24d±0.87d。结果显示,多拉菌素在猪体内具有吸收分布迅速、体内分布容积大、消除缓慢和生物利用度相对较高的特点,并表现为显著的长效性。研究结果对认识多拉菌素在猪体内的动力学特征和指导临床用药具有重要意义。     

多拉菌素浇泼剂对犬螨病的疗效观察

研究分析多拉菌素浇泼剂治疗犬螨病的临床效果。方法：选择西北农林科技大学2014年12月至2015年12月接收的患犬螨病的病犬60例作为研究对象,将病犬分为四组,甲组、乙组、丙组和对照组,均为15例,甲组、乙组、丙组病犬分别使用0.8 mg/kg、0.5 mg/kg、0.3 mg/kg的多拉菌素浇泼剂进行治疗,对照组病犬应用多拉菌素注射液进行治疗,对四组治疗效果进行比较分析。结果：甲组治疗1周、2周的有效率与乙组、丙差异并不大,无统计学意义（P>0.05）;甲组、乙组治疗1周、2周的有效率明显高于丙组,有统计学意义（P<0.05）。结论：适量的多拉菌素浇泼剂可有效治疗犬螨病,给药方便,值得推广应用。     

多拉菌素在猪体内的药代动力学

对多拉菌素在猪体内进行为期45d的药代动力学研究。长白×杜洛克杂交猪10头,临床健康,驱净寄生虫,体重36～50kg,以300μg/kg体重剂量分别通过静脉和肌肉注射给药。动物给药后在不同时间内分点经颈静脉采血。血浆样品用乙腈沉淀处理,上清液过C18富集柱,用甲醇提取多拉菌素并进行衍生化反应,以反向HPLC测定猪血清中的药物浓度。药代动力学参数用计算机程序MCPKP进行处理。结果表明,动物经静脉和肌肉注射给药后,血浆药物浓度分别可测至30d和25d,2种途径的药物浓度时间曲线均符合二室开放模型。主要药代动力学参数为:静脉注射T1/2α(1.092±0.66)d,T1/2β(6.11±2.73)d,AUC(274.19±119.89)μg/(L·d);肌肉注射T1/2α(0.056±0.022)d,T1/2β(3.20±1.34)d,AUC(223.51±65.20)μg/(L·d),CMAX(28.99±10.69)μg/L,Tp(1.24±0.87)d。多拉菌素肌肉注射的生物利用度为81.5%。结果显示多拉菌素在猪体内具有吸收分布较迅速、体内分布容积大、消除缓慢和生物利用度相对较高的特点,提示多拉菌素在猪体内作用的长效性主要由该化合物的自身特性所决定,而与给药途径和使用的溶剂关系不大,研究结果对指导临床正确用药具有重要意义。     

联合应用阿苯达唑和伊维菌素在线虫感染鄂尔多斯细毛羊体内的药动学研究

为阐明联合应用阿苯达唑(ABZ)和伊维菌素(IVM)在胃肠道线虫感染鄂尔多斯细毛羊体内的药动学互作关系,以感染胃肠道线虫的鄂尔多斯细毛羊为研究对象,比较研究了单独或联合应用阿苯达唑和伊维菌素后的药物动力学特征。通过粪便虫卵检查法,选取感染胃肠道线虫的鄂尔多斯细毛羊15只,随机分成3组,每组5只。第1组口服给予阿苯达唑(15mg/kg),第2组皮下注射伊维菌素(0.2mg/kg),第3组皮下注射伊维菌素(0.2mg/kg)的同时口服阿苯达唑(15mg/kg)。于给药后不同时间,由颈静脉采集血样,分离血浆,并用高效液相色谱法测定各时间点血浆阿苯达唑、阿苯达唑亚砜、阿苯达唑砜和伊维菌素浓度,并用PK Solution 2.0药物动力学软件计算出各药动学参数。结果表明,联合用药组绵羊血浆伊维菌素峰浓度(Cmax)、药时曲线下面积(AUC)和平均滞留时间(MRT)分别为44.80ng/mL±6.12ng/mL、5 007.46ng.h/mL±1 301.42ng.h/mL和85.47h±5.03h,均显著(P<0.05)小于单独用药组的对应参数值67.62ng/mL±9.06ng/mL、7 125.08ng.h/mL±908.52ng.h/mL和113.39h±9.00h。口服阿苯达唑组绵羊血浆中仅检测到了阿苯达唑砜和阿苯达唑亚砜,而未检测到阿苯达唑母药。联合用药后,除阿苯达唑砜的达峰时间(T max)显著推迟外,阿苯达唑砜和阿苯达唑亚砜的其他各参数之间均无显著性差异。因此,联合应用IVM和ABZ可影响它们在胃肠道线虫感染鄂尔多斯细毛羊体内的药动学特征,且对伊维菌素药动学特征的影响尤为明显,在临床联合用药过程中应予以重视。     

多拉菌素骨架缓释片在仔猪体内的药代动力学研究

为了研究多拉菌素骨架缓释片在仔猪体内的药代动力学特征,试验将20头仔猪随机分为缓释片组与常规片组,每组10头猪,分别口服多拉菌素骨架缓释片及常规片,于给药后第0. 5小时、1小时、2小时、4小时、6小时、8小时、12小时、18小时、1天、1. 5天、2天、3天、4天、5天、6天、7天采血,制备血浆,建立多拉菌素血浆样品的处理方法,采用高效液相色谱法测定其血药浓度,考察该方法的专属性并用PKSolver药动学药效学数据处理软件计算药动学参数。结果表明:多拉菌素在0. 5～50. 0 ng/m L之间呈良好的线性关系,回归方程:y=3. 210 3x-0. 018 2,R2=0. 999 7(n=7),建立的血浆处理及分析方法日内变异系数≤4. 72%,日间变异系数≤6. 33%;样品的平均回收率为93. 3%～95. 1%,完全符合生物样品分析要求;两组药的药动学行为均符合一级吸收二室模型,其主要药动学参数为:达峰时间(Tmax)分别为(0. 87±0. 03) d、(0. 85±0. 05) d;峰浓度(Cmax)分别为(27. 71±0. 92) ng/m L、(25. 64±1. 38) ng/m L;半衰期(T1/2)分别为(3. 43±0. 13) d、(2. 15±0. 11) d;药时曲线下面积(AUC0-t)达(223. 55±18. 17),(178. 41±14. 42) ng/(d·m L)。对两试验组AUC0-t、Cmax、Tmax进行差异性分析,三种药动学参数组间差异均极显著(P0. 01),且多拉菌素骨架缓释片与多拉菌素常规片的相对生物利用度为125%。说明多拉菌素骨架缓释片具有吸收好、消除慢、生物等效性高等特点。     

牦牛主要寄生虫病高效低残留防治技术研究(下)

为制定埃普利诺菌素(EPR)休药期及建立牦牛主要寄生虫病高效低残留防治技术提供科学依据。采用荧光高效液相色谱法(HPLC-FLD)检测埃普利诺菌素(EPR)浇泼剂在牦牛组织中的残留消除规律。结果:给牦牛按推荐剂量0.5mg.kg~(-1)给予EPR浇泼剂后,EPR在牦牛体内分布广泛,牦牛组织中EPR于2d达到最高浓度,之后浓度逐渐下降,药物浓度由高至低依次为肝脏、肾脏、脂肪、肌肉组织,浇泼部位肌肉与后腿肌肉药物残留量无差异,肝脏是EPR作用的靶组织,检出药物浓度由高到低分别为肝脏1050.50ng.g~(-1)、肾脏139.47ng.g~(-1)、脂肪20.76ng.g~(-1)、血浆10.24ng.g~(-1)、后腿肌肉5.63ng.g~(-1)、背部肌肉5.00ng.g~(-1)。第9d组织中残留量为肝脏505.12ng.g~(-1),肾脏66.23ng.g~(-1),脂肪14.87ng.g~(-1),血浆4.09ng.g~(-1),肌肉2.41～2.47ng.g~(-1)。略低于欧盟(EU)、国际食品法典委员会(CAC)规定的标准。研究结果表明,EPR浇泼剂0.5mg.kg~(-1)推荐剂量用于泌乳牦牛无需弃奶期,牦牛肉用时无需休药期或建议休药期为1d。为建立牦牛主要寄生虫病高效低残留防治技术提供了依据。     

多拉菌素浇泼剂对小鼠旋毛虫的疗效研究

研究了多拉菌素浇泼剂对小鼠旋毛虫各个时期的驱杀效果。采用多拉菌素浇泼剂按5mg·kg^-1·bw^-1为小鼠背部浇泼给药一次,对小鼠旋毛虫成虫、移行期幼虫和包囊期幼虫进行驱杀。结果表明。多拉菌素浇泼剂对旋毛虫成虫的杀虫效果最好,杀虫率可达99．5％,其次是旋毛虫的移行期幼虫,杀虫效果达96．62％,而对包囊期幼虫的杀虫效果最差,只有31．98％。多拉菌素浇泼剂治疗小鼠旋毛虫的成虫和移行期蚴虫疗效显著,而对包囊期幼虫效果不明显。本研究为该药进一步的广泛应用于家畜提供理论与试验依据。     

牦牛主要寄生虫病高效低残留防治技术研究(中)

为制定埃普利诺菌素(EPR)休药期及建立牦牛主要寄生虫病高效低残留防治技术提供科学依据。采用荧光高效液相色谱法(HPLC-FLD)检测埃普利诺菌素(EPR)注射剂在牦牛奶中的残留消除规律。结果表明:给泌乳牦牛皮下注射EPR注射液0.2mg·kg^-1剂量,EPR在牛奶中分布浓度较低,在给药后54.00h,牛奶中的EPR浓度达到峰值7.38±2.61ng·mL^-1,该值低于美国规定的EPR在牛奶中的最高残留限量(12ng·mL^-1)和欧盟及联合国粮食与农业组织(FAO)规定的EPR在牛奶中的最高残留限量(20ng·mL^-1)。给泌乳牦牛皮下注射EPR注射液0.4mg·kg^-1剂量,EPR在牛奶中分布浓度较低,在给药后42.00 h,牛奶中的EPR浓度达到峰值8.42±4.62 ng·mL^-1,最高值低于欧盟和联合国粮食与农业组织(FAO)规定的EPR在牛奶中的最高残留限量(20 ng·mL^-1),略高于美国规定的EPR在牛奶中的最高残留限量(12ng·mL^-1);在给药后56.00 h,牛奶中的EPR浓度达到峰值6.98±2.98 ng·mL^-1,该值低于美国规定的EPR在牛奶中的最高残留限量(12ng·mL^-1)和欧盟及联合国粮食与农业组织(FAO)规定的EPR在牛奶中的最高残留限量(20ng·mL^-1)。国产药物试验组与进口商品化制剂对照组的两种EPR浇泼剂在牦牛血浆中的残留消除规律,分别于1.67±0.2d与1.83±0.61d(Tmax)在血浆中达到最高药物浓度(Cmax)7.88±2.68ng·mL^-1与5.94±2.80ng·mL^-1,两种EPR制剂的生物等效性无显著性差异。国产和进口两种制剂的残留均低于联合国粮食与农业组织(FAO)所规定的最高残留限量(20ng·mL^-1)。研究结果表明,EPR注射剂0.2mg·kg^-1、0.4mg·kg^-1,EPR浇泼剂0.5mg·kg^-1推荐剂量用于泌乳牦牛无需弃奶期,牦牛乳用时无需休药期或建议休药期为1d。为建立牦牛主要寄生虫病高效低残留防治技术提供了依据。     

多拉菌素对昆明小鼠血液生化及常规指标影响的研究

为了进一步检测多拉菌素浇泼剂应用的安全性,试验检测了多拉菌素浇泼剂对小鼠外周血谷丙转氨酶(ALT)、谷草转氨酶(AST)、总蛋白(TP)、尿素氮(BUN)、肌酐(CRE)、碱性磷酸酶(ALP)、乳酸脱氢酶(LDH)、肌酸激酶(CK-NAC)指标及外周血常规指标的影响。结果表明:多拉菌素浇泼剂高、中、低三个剂量组小鼠血清中的ALT、AST、TP、BUN、CRE、ALP、LDH、CK-NAC等生化指标与对照组相比均无显著性差异。在治疗量(5 mg/kg)和3倍治疗量(15 mg/kg)时,多拉菌素对外周血白细胞总数和淋巴细胞比例有正面影响,在一定程度上能提高小鼠的非特异性免疫应答。说明多拉菌素浇泼剂对小鼠的各个器官、组织和代谢无损伤性作用和不良影响,对小鼠的免疫功能没有不良影响。     

Pharmacokinetics of Eprinomectin in Plasma and Milk following Subcutaneous Administration to Lactating Dairy Cattle

Eprinomectin is only available as a topically applied anthelmintic for dairy cattle. To determine whether eprinomectin can be applied as an injectable formulation in dairy cattle, a novel injectable formulation was developed and was subcutaneously delivered to four lactating dairy cattle at a dose rate of 0.2 mg/ kg. Plasma and milk samples were collected. The concentrations of eprinomectin in all samples were determined by HPLC. The peak plasma concentration (C_max)of 44.0±24.2 ng/ml occurred 39±19.3 h after subcutaneous administration, equivalent to the C_max (43.76±18.23 ng/ml) previously reported for dairy cattle after a pour-on administration of 0.5 mg/kg eprinomectin. The area under the plasma concentration–time curve (AUC) after subcutaneous administration was 7354±1861 (ng h)/ml, higher than that obtained after pour-on delivery (5737.68±412.80 (ng h)/ml). The mean residence time (MRT) of the drug in plasma was 211±55.2 h. Eprinomectin was detected in the milk at the second sampling time. The concentration of drug in milk was parallel to that in plasma, with a milk to plasma ratio of 0.16±0.01. The highest detected concentration of eprinomectin in milk was 9.0 ng/ml, below the maximum residue limit (MRL) of eprinomectin in milk established by the Joint FAO/WHO Expert Committee on Food Additives in 2000. The amount of eprinomectin recovered in the milk during this trial was 0.39%±0.08% of the total administered dose. This study demonstrates that subcutaneous administration of eprinomectin led to higher bioavailability and a lower dose than a pour-on application, and that an injectable formulation of eprinomectin may be applied in dairy cattle with a zero withdrawal period.     

Estimated plasma bupivacaine concentration after single dose and eight-hour continuous intra-articular infusion of bupivacaine in normal dogs

Objective— To estimate maximum plasma concentration (C_max) and time to maximum plasma (t_max) bupivacaine concentration after intra‐articular administration of bupivacaine for single injection (SI) and injection followed by continuous infusion (CI) in normal dogs. Study Design— Cross‐over design with a 2‐week washout period. Animals— Healthy Coon Hound dogs (n=8). Methods— Using gas chromatography/mass spectrometry, canine plasma bupivacaine concentration was measured before and after SI (1.5 mg/kg) and CI (1.5 mg/kg and 0.3 mg/kg/h). Software was used to establish plasma concentration–time curves and estimate C_max, T_max and other pharmacokinetic variables for comparison of SI and CI. Results— Bupivacaine plasma concentration after SI and CI best fit a 3 exponential model. For SI, mean maximum concentration (C_max, 1.33±0.954 μg/mL) occurred at 11.37±4.546 minutes. For CI, mean C_max (1.13±0.509 μg/mL) occurred at 10.37±4.109 minutes. The area under the concentration–time curve was smaller for SI (143.59±118.390 μg/mL × min) than for CI (626.502±423.653 μg/mL × min, P=.02) and half‐life was shorter for SI (61.33±77.706 minutes) than for CI (245.363±104.415 minutes, P=.01). The highest plasma bupivacaine concentration for any dog was 3.2 μg/mL for SI and 2.3 μg/mL for CI. Conclusion— Intra‐articular bupivacaine administration results in delayed absorption from the stifle into the systemic circulation with mean C_max below that considered toxic and no systemic drug accumulation. Clinical Relevance— Intra‐articular bupivacaine can be administered with small risk of reaching toxic plasma concentrations in dogs, though toxic concentrations may be approached. Caution should be exercised with multimodal bupivacaine administration because plasma drug concentration may rise higher than with single intra‐articular injection.     

Pharmacokinetics of ketamine in plasma and milk of mature Holstein cows

Sellers, G., Lin, H. C., G. Riddell, M. G., Ravis, W. R., Lin, Y. J., Duran, S. H., Givens, M.D. Pharmacokinetics of ketamine in plasma and milk of mature Holstein cows. J. vet. Pharmacol. Therap. 33 , 480–484. The purpose of this study was to evaluate the pharmacokinetics of ketamine in mature Holstein cows following administration of a single intravenous (i.v.) dose. Plasma and milk concentrations were determined using a high‐performance liquid chromatography assay. Pharmacokinetic parameters were estimated using a noncompartmental method. Following i.v. administration, plasma T_max was 0.083 h and plasma C_max was 18 135 ± 22 720 ng/mL. Plasma AUC was 4484 ± 1,398 ng·h/mL. Plasma t_½β was 1.80 ± 0.50 h and mean residence time was 0.794 ± 0.318 h with total body clearance of 1.29 ± 0.70 L/h/kg. The mean plasma steady‐state volume of distribution was calculated as 0.990 ± 0.530 L/kg and volume of distribution based on area was calculated as 3.23 ± 1.51 L/kg. The last measurable time for ketamine detection in plasma was 8.0 h with a mean concentration of 24.9 ± 11.8 ng/mL. Milk T_max was detected at 0.67 ± 0.26 h with C_max of 2495 ± 904 ng/mL. Milk AUC till the last time was 6593 ± 2617 ng·h/mL with mean AUC milk to AUC plasma ratio of 1.99 ± 2.15. The last measurable time that ketamine was detected in milk was 44 ± 10.0 h with a mean concentration of 16.0 ± 9.0 ng/mL.     

Pharmacokinetic modeling and Monte Carlo simulation of ondansetron following oral administration in dogs

Ondansetron is a potent antiemetic drug that has been commonly used to treat acute and chemotherapy‐induced nausea and vomiting (CINV) in dogs. The aim of this study was to perform a pharmacokinetic analysis of ondansetron in dogs following oral administration of a single dose. A single 8‐mg oral dose of ondansetron (Zofran^®) was administered to beagles (n = 18), and the plasma concentrations of ondansetron were measured by liquid chromatography‐tandem mass spectrometry. The data were analyzed by modeling approaches using ADAPT5, and model discrimination was determined by the likelihood‐ratio test. The peak plasma concentration (C_max) was 11.5 ± 10.0 ng/mL at 1.1 ± 0.8 h. The area under the plasma concentration vs. time curve from time zero to the last measurable concentration was 15.9 ± 14.7 ng·h/mL, and the half‐life calculated from the terminal phase was 1.3 ± 0.7 h. The interindividual variability of the pharmacokinetic parameters was high (coefficient of variation > 44.1%), and the one‐compartment model described the pharmacokinetics of ondansetron well. The estimated plasma concentration range of the usual empirical dose from the Monte Carlo simulation was 0.1–13.2 ng/mL. These findings will facilitate determination of the optimal dose regimen for dogs with CINV.     

Pharmacokinetics studies of enrofloxacin injectable in situ forming gel in dogs

The objective of this study was to evaluate the pharmacokinetic characteristics of enrofloxacin (ENR) injectable in situ gel we developed in dogs following a single intramuscular (i.m.) administration. Twelve healthy dogs were randomly divided into two groups (six dogs per group), then administrated a single 20 mg/kg body weight (b.w.) ENR injectable in situ gel and a single 5 mg/kg b.w. ENR conventional injection, respectively. High‐performance liquid chromatography (HPLC) was used to determine ENR plasma concentrations. The pharmacokinetic parameters of ENR injectable in situ gel and conventional injection in dogs are as follows: MRT (mean residence time) (45.59 ± 14.05) h verse (11.40 ± 1.64) h, AUC (area under the blood concentration vs. time curve) (28.66 ± 15.41) μg·h/mL verse (11.06 ± 3.90) μg·h/mL, c_max (maximal concentration) (1.59 ± 0.35) μg/mL verse (1.46 ± 0.07) μg/mL, t_max (time needed to reach c_max) (1.25 ± 1.37) h verse (1.40 ± 0.55) h, t_1/2λz (terminal elimination half‐life) (40.27 ± 17.79) h verse (10.32 ± 0.97) h. The results demonstrated that the in situ forming gel system could increase dosing interval of ENR and thus reduced dosing frequency during long‐term treatment. Therefore, the ENR injectable in situ gel seems to be worth popularizing in veterinary clinical application.     

Hematological adverse effects and pharmacokinetics of ribavirin in pigs following intramuscular administration

Ribavirin (RBV) is a synthetic guanosine analog that is used as a drug against various viral diseases in humans. The in vitro antiviral effects of ribavirin against porcine viruses were demonstrated in several studies. The purposes of this study were to evaluate the adverse effects and pharmacokinetics of ribavirin following its intramuscular (IM) injection in pigs. Ribavirin was formulated as a double‐oil emulsion (RBV‐DOE) and gel (RBV‐Gel), which were injected into the pigs as single‐dose IM injections. After injection of RBV, all of the pigs were monitored. The collected serum and whole blood samples were analyzed by liquid chromatography–tandem mass spectrometry and complete blood count analysis, respectively. All of the ribavirin‐treated pigs showed significant decreases in body weight compared to the control groups. Severe clinical signs including dyspnea, anorexia, weakness, and depression were present in ribavirin‐treated pigs until 5 days postinjection (dpi). The ribavirin‐treated groups showed significant decrease in the number of red blood cells and hemoglobin concentration until 8 dpi. The mean half‐life of the RBV‐DOE and RBV‐Gel was 27.949 ± 2.783 h and 37.374 ± 3.502 h, respectively. The mean peak serum concentration (C_max) and area under the serum concentration–time curve from time zero to infinity (AUC_inf) of RBV‐DOE were 8340.000 ± 2562.577 ng/mL and 16 0095.430 ± 61 253.400 h·ng/mL, respectively. The C_max and AUC_inf of RBV‐Gel were 15 300.000 ± 3764.306 ng/mL and 207526.260 ± 63656.390 h·ng/mL, respectively. The results of this study provided the index of side effect and pharmacokinetics of ribavirin in pigs, which should be considered before clinical application.     

Comparative plasma disposition kinetics of ivermectin, moxidectin and doramectin in cattle

The persistence of the broad-spectrum antiparasitic activity of endectocide compounds relies on their disposition kinetics and pattern of plasma/tissues exchange in the host. This study evaluates the comparative plasma disposition kinetics of ivermectin (IVM), moxidectin (MXD) and doramectin (DRM) in cattle treated with commercially available injectable formulations. Twelve (12) parasite-free male Hereford calves (180–210 kg) grazing on pasture were allocated into three groups of four animals each. Animals in each group received either IVM (Ivomec 1%, MSD AGVET, Rahway, NJ, USA), MXD (Cydectin 1%, American Cyanamid, Wayne, NJ, USA) or DRM (Dectomax 1%, Pfizer Inc., New York, NY, USA) by subcutaneous injection at a dose of 200 μg/kg. Jugular blood samples were collected from 1 h up to 80 days post-treatment, and plasma extracted, derivatized and analysed by high performance liquid chromatography (HPLC) using fluorescence detection. The parent molecules were detected in plasma between 1 h and either 70 (DRM) or 80 (IVM and MXD) days post-treatment. The absorption of MXD from the site of injection was significantly faster (absorption half-life (t_½ab) = 1.32 h) than those of IVM (t_½ab= 39.2 h) and DRM (t_½ab= 56.4 h). MXD peak plasma concentration (C_max) was reached significantly earlier (8.00 h) compared to those of IVM and DRM (4–6 days post-treatment). There were no differences on C_max values; the area under the concentration–time curve (AUC) was higher for IVM (459 ng.d/mL) and DRM (627 ng.d/mL) compared to that of MXD (217 ng.d/mL). The mean plasma residence time was longer for MXD (14.6 d) compared to IVM (7.35 d) and DRM (9.09 d). Unidentified metabolites were detected in plasma; they accounted for 5.75% (DRM), 8.50% (IVM) and 13.8% (MXD) of the total amount of their respective parent drugs recovered in plasma. The comparative plasma disposition kinetics of IVM, MXD and DRM in cattle, characterized over 80 days post-treatment under standardized experimental conditions, is reported for the first time.     

Pharmacokinetics of cefpodoxime in plasma and subcutaneous fluid following oral administration of cefpodoxime proxetil in male beagle dogs

Kumar, V., Madabushi, R., Lucchesi, M. B. B., Derendorf, H. Pharmacokinetics of cefpodoxime in plasma and subcutaneous fluid following oral administration of cefpodoxime proxetil in male beagle dogs. J. vet. Pharmacol. Therap. 34 , 130–135. Pharmacokinetics of cefpodoxime in plasma (total concentration) and subcutaneous fluid (free concentration using microdialysis) was investigated in dogs following single oral administration of prodrug cefpodoxime proxetil (equivalent to 5 and 10 mg/kg of cefpodoxime). In a cross over study design, six dogs per dose were utilized after a 1 week washout period. Plasma, microdialysate, and urine samples were collected upto 24 h and analyzed using high performance liquid chromatography. The average maximum concentration (C_max) of cefpodoxime in plasma was 13.66 (±6.30) and 27.14 (±4.56) μg/mL with elimination half‐life (t_1/2) of 3.01 (±0.49) and 4.72 (±1.46) h following 5 and 10 mg/kg dose, respectively. The respective average area under the curve (AUC_0–∞) was 82.94 (±30.17) and 107.71 (±30.79) μg·h/mL. Cefpodoxime was readily distributed to skin and average free C_max in subcutaneous fluid was 1.70 (±0.55) and 3.06 (±0.93) μg/mL at the two doses. Urinary excretion (unchanged cefpodoxime) was the major elimination route. Comparison of subcutaneous fluid concentrations using pharmacokinetic/pharmacodynamic indices of fT_>MIC indicated that at 10 mg/kg dose; cefpodoxime would yield good therapeutic outcome in skin infections for bacteria with MIC₅₀ upto 0.5 μg/mL while higher doses (or more frequent dosing) may be needed for bacteria with higher MICs. High urine concentrations suggested cefpodoxime use for urinary infections in dogs.     

Disposition and safety of zonisamide after intravenous and oral single dose and oral multiple dosing in normal hound dogs

The purpose of this study was to determine an oral dosing regimen of zonisamide in healthy dogs such that therapeutic concentrations would be safely reached and maintained at steady‐state. Adult hound dogs (n = 8) received a single IV (6.9) and an oral (PO) dose (10.3 mg/kg) using a randomized cross‐over design. Zonisamide was then administered at 10.3 mg/kg PO every 12 h for 8 weeks. Zonisamide was quantitated in blood compartments or urine by HPLC and data were subjected to noncompartmental pharmacokinetic analysis. Comparisons were made among blood compartments (one‐way anova ; P ≤ 0.05). Differences among blood compartments occurred in all derived pharmacokinetic paramenters for each route of administration after single and multiple dosing. After single PO dosing, plasma C_max was 14.4 ± 2.3 mcg/mL and elimination half‐life was 17.2 ± 3.6 h. After IV dosing, volume of distribution was 1.1 ± 0.25 L/kg, clearance was 58 ± 11 mL/h/kg and elimination t_1/2 was 12.9 ± 3.6 h. Oral bioavailability was 68 ± 12%; fraction of unbound drug approximated 60%. At steady‐state (4 days), differences occurred for for all parameters except C_max and C_min. Plasma C_max at steady‐state was 56 ± 12 mcg/mL, with 10% fluctuation between C_max and C_min. Plasma t_1/2 (h) was 23.52 ± 5.76 h. Clinical laboratory tests remained normal, with the exception of total T4, which was below normal limits at study end. In conclusion, 10 mg/kg twice daily results in peak plasma zonisamide which exceeds the recommended human therapeutic range (10 to 40 μg/mL) and is associated with suppression of thyroid hormone synthesis. A reasonable b.i.d starting dose for canine epileptics would be 3 mg/kg. Zonisamide monitored in either serum or plasma should be implemented at approximately 7 days.