The construction and application of a population physiologically based pharmacokinetic model for methadone in Beagles and Greyhounds

Methadone is an opioid analgesic in veterinary and human medicine. To help develop appropriate pain management practices and to develop a quantitative model for predicting methadone dosimetry, a flow‐limited multiroute physiologically based pharmacokinetic (PBPK) model for methadone in dogs constructed with Berkeley Madonna? was developed. The model accounts for intravenous (IV), subcutaneous (SC), and oral administrations, and compartmentalizes the body into different components. This model was calibrated from plasma pharmacokinetic data after IV administration of methadone in Beagles and Greyhounds. The calibrated model was evaluated with independent data in both breeds of dogs. One advantage of this model is that most physiological parameter values for Greyhounds were taken directly from the original literature. The developed model simulates available pharmacokinetic data for plasma concentrations well for both breeds. After conducting regression analysis, all simulated datasets produced an R ² > 0.80 when compared to the measured plasma concentrations. Comparative analysis of the dosimetry of methadone between the breeds suggested that Greyhounds had ~50% lower 24‐hr area under the curve (AUC) of plasma or brain concentrations than in Beagles. Furthermore, population analysis was conducted with this study. This model can be used to predict methadone concentrations in multiple dog breeds using breed‐specific parameters.     

1-MCP在果蔬体内的药代规律研究及产品开发进展

1-甲基环丙烯(1-MCP)是一种乙烯受体抑制剂,广泛应用于果蔬采后贮藏保鲜行业.本文从1-MCP在果蔬体内的吸收、与果实内部生物大分子互作及其机制、残留量及其法规约定等方面对1-MCP在果蔬体内的药代规律进行了分析.从产品开发和技术应用的角度概括了1-MCP常见的产品形式和发展趋势,梳理了1-MCP与预冷技术结合、与杀菌剂联用、与果蔬风味形成调控技术复合使用等多效保鲜技术的研发情况.通过概括分析可以发现,1-MCP的安全性高,残留量低,但有关其在果蔬体内的代谢规律和对果蔬品质的不利影响方面的研究较少,且大部分的研究集中于1-MCP的应用,长效稳定缓释剂型和复合保鲜技术将是今后的发展趋势.     

恩诺沙星在鲤体内的药效学及药动力学研究

用恩诺沙星对5种淡水养殖鱼类常见病、多发病致病菌进行抑菌试验,获得了恩诺沙星对细菌出血性败血病、打印病、赤皮病、烂鳃病、肠炎病致病菌的最小抑菌浓度(MIC)分别为0 02、0 04、0 63、0 31、0 04μg/mL。体内抗菌药效试验结果表明,每日以10mg/kg剂量混饲口灌给药,能有效地杀灭致病菌,提高感染鱼的成活率。并应用高效液相色谱(HPLC)法测定以该剂量给药后不同时间鱼血浆中药物的质量浓度。采用MCPKP药代动力学软件处理药时数据,获得了鲤对恩诺沙星的吸收、分布与排除数据,结果表明,混饲口灌恩诺沙星在鱼体内的药时数据符合开放式一室模型,=0 2015h,t1/2K=主要药代动力学参数:AUC=45 0550μg/(mL·h),Cmax=2 1472μg/mL,t1/2Ka13 6513h。     

诺氟沙星在淡水青虾体内药物代谢动力学研究

在（26±1）℃的水温条件下,青虾一次性肌肉注射25mg／kg诺氟沙星后,用反相高效液相色谱法测定青虾血淋巴和肌肉组织中诺氟沙星含量。青虾血淋巴药一时曲线和肌肉药一时曲线均可以用二室开放模型来描述,诺氟沙星在青虾血淋巴液中的主要药动学参数为：分布相半衰期t1/α为1．66h,消除相半衰期t1/β为1．69h,达峰时间T（Peak）为1．82h,峰浓度C（max）为6．0081μg/mL,曲下面积AUC为30．75μg·mL^-1·h^-1,吸收相半衰期t1/2ka为1．66h。肌肉中的主要药动学参数为：分布相半衰期t1/ks为0．08h,消除相半衰期t1/2β为4．42h,达峰时间狄Peak）为0．03h,峰浓度C（max）为16．72μg/mL,曲下面积AUC为12．34μg·mL^-1·h^-1,吸收相半衰期t1/2a为0．08h。结果表明青虾肌注诺氟沙星后,能比较迅速的被吸收,并且在组织中维持较高的药物浓度。     

Clinical pharmacology of clemastine in healthy dogs

The pharmacokinetic properties of clemastine were investigated in six healthy dogs and compared with the effect of the drug recorded as inhibition of wheal formation induced by intradermal injections of histamine. Clemastine clearance was high (median: 2.1 L h(-1) kg(-1)) and the volume of distribution large (13.4 L kg(-1)). The half-life after intravenous administration was 3.8 h and the plasma protein binding level in vitro was 98%. After oral administration, the bioavailability was only 3%. Given intravenously, clemastine (0.1 mg kg(-1)) inhibited wheal formation completely for 7 h, whereas the effect after oral administration (0.5 mg kg(-1)) was minor. The data show that most dosage regimens suggested in the literature for the oral administration of clemastine to dogs are likely to give too low a systemic exposure of the drug to allow effective therapy.     

阿维菌素在草鱼体内的药物代谢动力学研究

【目的】研究阿维菌素在草鱼体内的药物代谢动力学,为实际生产中阿维菌素的使用提供理论指导。【方法】用初始质量浓度为0.3 μg/L的阿维菌素水溶液药浴草鱼,于给药后0.5,1,2,3,4,6,8,10,12,24,48,72,96,144,216,336,528和576 h采取血浆、肌肉+皮、肝脏、肾脏、鳃等样品,采用高效液相色谱荧光法测定阿维菌素在草鱼血浆中的质量浓度及在组织中的含量,数据经3P97药动学软件分析。【结果】在(26.0±1.0) ℃的水温条件下,阿维菌素单剂量浸泡给药0.3 μg/L,血药经时过程符合二室开放式模型。主要药动学参数如下：分布半衰期(T_1/2α)34.2 h,吸收半衰期(T_1/2(ka))15.61 h,消除半衰期(T_1/2β)163.22 h,药时曲线下面积(AUC)2 486.02 (μg·h)/L,达峰时间(T_peak)40.75 h,峰质量浓度(C_max)11.92 μg/L。药后72 h时草鱼肌肉、肝脏、肾脏和鳃中阿维菌素含量均达到最高值,其中肝脏中的含量最高,达到17.8 μg/kg,其后依次为肾脏(12.1 μg/kg)、肌肉(10.7 μg/kg)和鳃组织(5.2 μg/kg),血浆中阿维菌素含量在48 h达到最高(11.2 μg/L)。肝脏、肾脏和鳃组织中阿维菌素含量均呈“双峰”曲线,前两者在144 h时都有第2次吸收高峰,分别为15.0和8.4 μg/kg。【结论】草鱼血浆及各组织中阿维菌素在给药后24 d未检出,考虑到临床应用情况的复杂性及理论值与实测值之间的差距,建议对草鱼单剂量(0.3 μg/L)药浴阿维菌素后的休药期为24 d。     

重组猪干扰素α1冻干粉针剂在猪体内的药代动力学研究

为研究重组猪干扰素α1 (rPoIFN-α1)冻干粉针剂在猪体内的药代动力学特征,本研究将实验猪随机分为3组:分别静脉、肌肉和皮下注射rPoIFN-α1 1.0×107 IU,每组设立对照组,于注射后间隔不同时间采血,采用细胞病变抑制法测定其血清样品中rPoIFN-α1的效价.结果表明,肌肉注射组和皮下注射组药动学特征符合一室开放模型,呈一级动力学消除,血药峰时间(Tmax)分别为2.872±0.314 h和4.000±0.539 h,消除半衰期(T1/2)分别为6.236±0.551 h和6.644±0.751 h,血药峰浓度(Cmax)分别为3.980±2.875× 104 IU/L和1.080±0.986× 104 IU/L.静脉注射组符合二室开放模型,呈一级动力学消除,分布半衰期(T1/2α)为0.136±0.021 h,消除半衰期(T1/2β)为5.195±0.351 h,Cmax值为6.380±0.546× 104 IU/L.rPoIFN-α1静脉、肌肉和皮下注射组清除率分别为0.930±0.132 L/h、0.677±0.228 L/h和0.879±0.210 L/h.与静脉注射组相比,肌肉注射组的生物利用度为47.82％,皮下注射组的生物利用度为35.09％.本实验结果提示这3种rPoIFN-α1的注射方法在猪体内吸收、消除较快,具有线性动力学特征.rPoIFN-α1肌肉注射给药的生物利用度高于皮下注射组,消除半衰期比静脉注射组延长,可以作为替代静脉注射的一种方便和安全给药途径.     

银黄颗粒中黄芩甙在大鼠体内的测定及药代动力学

目的：考察银黄制剂的药动学特征。方法：建立测定大鼠血浆中黄芩甙的高效液相色谱法（HPLC）,并以银黄颗粒为代表进行药代动力学研究。结果：黄芩甙经直肠灌注比灌胃血药浓度高、消除速率慢;黄芩甙经灌胃会产生首过代谢作用,同时在用药后约600min出现双峰现象;银黄颗粒中的黄芩甙受其它成分的影响不明显,在大鼠体内的药动学过程与单体黄芩甙基本一致。结论：用建立的HPLC法进行银黄颗粒的药代动力学研究,方法简单、准确、快速。并且获得的药代动学参数具有一定临床应用价值。     

Pharmacokinetics and physiologic/behavioral effects of buprenorphine administered sublingually and intravenously to neonatal foals

Buprenorphine is absorbed following sublingual administration, which would be a low‐stress delivery route in foals. However, the pharmacokinetics/pharmacodynamics are not described in foals. Six healthy foals <21 days of age participated in a blinded, randomized, 3‐period, 5‐sequence, 3‐treatment crossover prospective study. Foals received 0.01–0.02 mg/kg buprenorphine administered SL or IV with an equivalent volume of saline administered by the opposite route. Blood was collected from the cephalic vein for pharmacokinetic analysis. Physiologic parameters (HR, RR, body temperature, GI sounds), locomotion (pedometer), and behavioral data (activity level, nursing time, response to humans) were recorded. Plasma concentration of buprenorphine exceeded a presumed analgesic level (0.6 ng/ml) in five foals in the IV group and one in the SL group but only for a very brief time. Pharmacokinetic analysis following IV administration demonstrated a short elimination half‐life (t_1/2β 1.95 ± 0.7 hr), large volume of distribution (6.46 ± 1.54 L/kg), and a high total clearance (55.83 ± 23.75 ml/kg/min), which differs from adult horses. Following SL administration, maximum concentrations reached were 0.61 ± 0.11 ng/ml and bioavailability was 25.1% ± 10.9%. In both groups, there were minor statistical differences in HR, RR, body temperature, locomotion, and time spent nursing. However, these differences were clinically insignificant in this single dose study, and excitement, sedation, or colic did not occur.     

伊维菌素和三氯苯达唑在羊体内的药动学相互作用

【目的】研究联合应用伊维菌素和三氯苯达唑在蠕虫感染绵羊体内的药代动力学特征及相互影响,【方法】借助经典麦克麦斯特法定量检查羊群消化道蠕虫感染基础上选取每克粪便虫卵数大于1500个,且感染强度相近的泌乳期鄂尔多斯细毛羊15只,平均体重为（39.3±3.2）kg,年龄为4周岁。将15只受试羊禁食8 h后随机分成3组,按照预定试验设计给予不同药物：第1组皮下注射伊维菌素（0.2 mg•kg-1）,第2组灌服三氯苯达唑混悬液（12 mg•kg-1）,第3组皮下注射伊维菌素（0.2 mg•kg-1）的同时灌服三氯苯达唑混悬液（12 mg•kg-1）。分别于给药后第0.75、2、4、8、16、24、36、48、72、120、192和336 h,由颈静脉采集5 mL血样,离心分离血浆,冷冻保存待测。建立检测血浆伊维菌素（IVM）、三氯苯达唑（TCBZ）及其主要活性代谢产物三氯苯达唑亚砜（TCBZSO）浓度的高效液相色谱（HPLC）荧光检测法和紫外检测法,并对每个样品进行甲醇沉淀蛋白,经ODS C18固相萃取柱进行纯化处理后,分别测定各组血浆样品中的IVM、TCBZ及其主要代谢产物TCBZSO的浓度。色谱条件：反相C18柱,InertsilODS-SP(5 µm,4.6×150 mm,I.D.);流动相为V(甲醇+乙腈)﹕V(水)=95﹕5;激发波长364 nm,发射波长470 nm;流速为1.0 mL•min-1;柱温为室温;进样量为20 µL。最后将测定血药浓度数据用Phoenix WinNonlin药动学软件按非房室模型方法处理,计算出各试验组每只羊的相关药动学参数,并进行统计学分析。 【结果】血浆样品色谱图中IVM和内标物AVM色谱峰分离良好,保留时间分别为8.73 min和6.16 min,且不受血浆其他干扰峰的影响;TCBZ和TCBZSO以及内标物甲苯咪唑的保留时间分别为10.04、5.53和3.42 min,且在试验分析条件下具有良好的分离度,血浆内源性物质对目标峰没有干扰。对HPLC检测方法的绝对回收率、精密度和准确度等的考证结果均达到色谱测定要求。因此,本试验所建立的方法切实可行,能满足测定血浆样品各目标物的检测要求。联合应用IVM和TCBZ后,IVM的血浆峰浓度(Cmax)和药时曲线下面积（AUC）极显著下降,表观分布容积（Vd）、消除半衰期（T1/2ke）和体清除率（CLb）反而极显著增加;联合用药后TCBZSO的Vd、MRT和Tmax显著高于单独用药组,T1/2ke则极显著高于单独用药组。【结论】为蠕虫感染绵羊联合应用伊维菌素和三氯苯达唑后,在药代动力学方面相互产生了负面影响,未达到联合用药的真正目的。由此可见,在临床实践中联合用药时应考虑它们的药动学相互作用问题,应避免只根据体外药效学协同作用进行盲目配伍和联合用药,从而保证充分发挥各药物的原有药效和协同作用的目的。