磺胺二甲嘧啶在麻黄鸡组织中残留消除规律研究

用添加临床剂量100 mg/kg磺胺二甲嘧啶的饲料喂养40日龄麻黄鸡,连续用药3 d,分别在停药0、12、24、48、72、96、120、144、192、240、360、480、600 h时间点对肌肉、肝和肾组织采样,检测磺胺二甲嘧啶残留浓度。停药25 d后,肌肉组织残留量为0.054 mg/kg,肝和肾组织未检出磺胺二甲嘧啶,结果表明磺胺二甲嘧啶在麻黄鸡组织中停药期为25 d,《中国兽药典》2005年版中规定磺胺二甲嘧啶10 d的停药期是不尽合理的。     

Sulfamethazine blood/tissue correlation study in swine

Seventy market-weight hogs (90 to 113 kg) were used in a feeding study to determine the correlation of serum sulfamethazine concentrations with sulfamethazine concentrations in liver and muscle at time of slaughter. Test groups were fed medicated feeds prepared from commercial medicated premixes containing 110 g of sulfamethazine/metric ton for 30 days. Fifteen days before hogs were slaughtered, test groups were given maintenance feeds containing 1.1 to 13.9 g of sulfamethazine/metric ton and were fed these diets until slaughtered. Comparison of data from positive- and negative-control groups indicated that total withdrawal of sulfamethazine in the feed was not necessary for the liver to contain less than the allowed tolerance of 0.1 mg of sulfamethazine/kg of liver at slaughter. Feed concentrations of up to 2 g of sulfamethazine/metric ton could be tolerated in withdrawal feeds before liver sulfamethazine values exceeded 0.1 mg/kg of liver. Serum/tissue sulfamethazine ratios were erratic in hogs given 1.1 to 2.7 g of sulfamethazine/metric ton, but became less variable in hogs given greater than 5.7 g/metric ton. Feed concentrations greater than 8 g of sulfamethazine/metric ton produced values greater than 0.1 mg/kg of muscle and values of about 0.4 mg/kg of liver. When serum sulfamethazine concentrations alone were used as a predictor for tissue sulfamethazine values, 100% of the liver values exceeded 0.10 mg/kg of liver when sulfamethazine in serum was greater than 0.45 mg/L. However, 57.4% of samples having serum concentrations between 0.10 and 0.45 mg/L had associated sulfamethazine values greater than 0.1 mg/kg of liver. All hogs having serum sulfamethazine concentrations less than 0.1 mg/L had sulfamethazine concentrations less than 0.1 mg/kg of liver.     

氟苯尼考注射液在鸡体内残留消除研究

［摘 要］为研究氟苯尼考注射液在鸡体内的残留消除规律。本实验采用35只约3kg左右的健康白羽鸡,随机分为2组,给药组30只,对照组5只。给药组用药量为20mg/kg/次,每隔48小时用药1次,连用2次,对照组不给任何抗菌药物,与给药组同环境饲养。在最后一次给药6h、24h(1天)、72h(3天)、120h(5天)、168h(7天)时采集肉、肝、肾、皮脂样本,经LC-MS/MS法测定组织中的氟苯尼考及其标示物氟苯尼考胺残留量,并利用WT1.4软件计算休药期。结果显示：氟苯尼考注射液在鸡肌肉、肝脏、肾脏及皮脂中的休药期分别是3.41d、2.06d、2.25d、1.47d。为保证兽药使用安全、消费者健康和食品安全,推荐氟苯尼考注射液在鸡体内的休药期为4d。     

Comparative pharmacokinetics of chlortetracycline in milk-fed versus conventionally fed calves

Plasma and tissue concentration and pharmacokinetics of chlortetracycline (CTC) was determined in milk-fed and conventionally fed Holstein calves. A two-compartment open model was used after a single intravenous dose (11 mgn CTC/kg body weight). There were no significant differences between dietary treatments. The drug was rapidly distributed from plasma into the peripheral compartment but was slowly eliminated, with detectable concentration of CTC continuing for 72 h after dosing. A single-compartment model was used after a single oral dose (22 mg CTC/kg body weight). All but four of the kinetic parameters were significantly different for the two dietary treatments. Milk-fed calves had a larger area under the plasma level curve, a larger fraction of the dose absorbed, a smaller volume of distribution and a smaller overall body clearance rate. Estimated recovery of CTC in the urine of the milk-fed calves was greater, regardless of route of administration. The concentration of CTC in tissues following an oral dose was greatest in kidney, followed by liver, heart, skeletal muscle, spleen and brain. Tissue depletion of CTC closely paralleled the decline in plasma concentration.     

Ceftiofur distribution in plasma and tissues following subcutaneously administration in ducks

A study was performed to determine the residues in blood and edible tissues of healthy ducks (25 days old, mean body weight 1.0+/-0.13 kg) after subcutaneous administration of ceftiofur sodium at a dose rate of 2 mg/kg body weight (Group I) and 4 mg/kg body weight (Group II). Blood, muscle, liver, kidney, and fat samples were collected from all of ducks on the 1st, 2nd, 3rd, 4th, and 5th day after treatment of drug, and ceftiofur was analyzed with a high-performance liquid chromatography (HPLC) assay with results reported as ceftiofur-free acid equivalent (CFAE). To study the spiked recovery, blank plasma and tissues were spiked with two different concentrations of ceftiofur sodium (0.1, 0.5 microg/g). Average recovery values for all samples ranged from 70.3 to 87.3%. In the group I, desfuroylceftiofur acetamide (DCA) was not detected in all of plasma, muscle, liver, and fat tissues on the 1st day after treatment. But, kidney samples on the 1st day were detected DCA (0.059+/-0.01 microg CFAE/g tissue). On the 2nd day of post-treatment, the concentrations of DCA in all tissues were lower than the detection limit, 0.05 microg CFAE /g tissue. In the group II on the 1st day after treatment, the concentration of DCA was 0.124+/-0.06 microg CFAE/g tissue, 0.103+/-0.03 microg CFAE/g tissue, and 0.071+/-0.010 microg CFAE/g tissue in plasma, kidney, and muscle samples, respectively. On the 2nd day after treatment of ceftiofur, the concentrations of DCA in all tissues were lower than 0.05 microg CFAE/g tissue. According to our results, the concentrations of DCA on the 1st day after treatment with 2 mg/kg body weight were below 0.05 microg CFAE/g tissue equivalent in all tissues except for kidney. On the 2nd day after administration at the dose of 4 mg/kg body weight, no DCA was also detected in all of the tissues although DCA was detected in all samples on the 1st day.     

Effect of trenbolone and testosterone on the plasma elimination rates of sulfamethazine, trimethoprim, and antipyrine in female dwarf goats

Plasma elimination rates of sulfamethazine (100 mg/kg of body weight, IV), trimethoprim (20 mg/kg, IV), and antipyrine (35 mg/kg, IV) were studied in adult female dwarf goats (n = 5) before and after implantation with trenbolone acetate (5 mg/kg). Pretreatment with trenbolone caused a significant decrease in the elimination rate of the drugs tested: for sulfamethazine, 5 times; for antipyrine, 3 times; and for trimethoprim, 2 times. After treatment with testosterone (1 mg/kg, SC, twice weekly for 2.5 weeks), female goats (n = 5) had a similar decrease in the elimination rate of sulfamethazine. Other induced effects included a change in social behavior, a lower voice, and the development of a typical billy goat-like odor. Plasma creatinine concentrations after androgen administration were significantly higher than those before androgen administration; changes were not observed in plasma urea values. Because of the differences observed, we believe that more attention should be paid to the effects of androgenic agents on drug kinetic properties, with particular reference to studies on clinical efficacy, side effects, and drug residues in food products.     

灰黄霉素在家兔组织中的分布及残留消除规律研究

研究灰黄霉素在家兔组织中的分布及消除规律,为灰黄霉素用于治疗家兔真菌病的安全性评价提供依据。选择42只新西兰白兔,于饲料中添加灰黄霉素（800g／1000kg）混饲,连续饲喂14d,分别于停药后1、3、5、7、9、14、21d,各处死6只,取其肝、肾、肌肉、皮肤及脑组织。以盐酸普萘洛尔为内标,二氯甲烷提取后用高效液相色谱-串联质谱仪（HPLC—MS／MS）进行各种组织中灰黄霉素浓度分析。结果显示,连续用药14d后,灰黄霉素在家兔组织中的分布情况为：肝组织浓度最高（134．61μg／kg）,肾组织次之（54．09μg／kg）,脑组织浓度最低（未检出）;停药后,随着时间的延长,灰黄霉素在肌肉、肝、肾和皮肤组织中的浓度逐渐下降,且在肝脏中的消除速度最快,停药21d后,灰黄霉素在肾组织中浓度为3．39μg／kg,在肝组织中浓度为12．36μg／kg,其他组织低于定量限或未检出。建议家兔生产中慎用灰黄霉素。     

Elimination of sulfamethazine residues from swine.

Tissue concentrations of sulfamethazine in swine fed the drug at the rate of 500 g/ton of ration (550 g/1,000 kg) for a 30-day period depleted to 0.1 ppm or less within 4 to 10 days after withdrawal of medicated feed. Depletion from the tissues and plasma of treated pigs showed a linear relationship with time when the concentrations were plotted on a semilogarithmic graph. Six untreated pigs that were placed on bedding in pens formerly occupied by the treated group developed tissue residues at or above 0.1 ppm sulfamethazine; the mean plasma concentration of sulfamethazine reached 2.8 ppm by day 15.     

Pharmacokinetics, safety and tissue residues of sustained-release sulfamethazine in sheep

Concentration-time profiles and the rates of absorption, extent of distribution and half-lives of sulfamethazine (SMZ), administered intravenously, orally as a water solution and as a sustained-release formulation (CalfSpan) were determined in 10 healthy sheep. The geometric mean half-life of elimination of i.v. SMZ was 10.8 h, compared to 14.3 h for the sustained-release preparation (CalfSpan) and 4.3 h for the oral water solution. Blood levels of SMZ were at or above 50 micrograms/ml for more than 48 h for CalfSpan, for 24 h after i.v. SMZ (100 mg/kg body wt), and for less than 24 h after p.o. SMZ (100 mg/kg body wt). The mean bioavailability of the oral SMZ solution was 58.3% (AUCp.o./AUCi.v.). The estimated bioavailability of the CalfSpan preparation was 52.5%. The safety of the sustained-release preparation was tested by dosing sheep with multiples (one, three and five times) of the recommended dose (one tablet, 8 g SMZ, per 20 kg body wt), once a day for 3 days. Clinical blood chemistries showed a significant increase in serum iron, and a decrease in serum phosphorus in animals treated at the 3x and 5x dose levels. Necropsies of the 5x dose animals did not show any gross signs that could be attributed to SMZ, and histological examination of tissues from the 5x animals revealed no organ pathology. Residues of SMZ in liver, fat, kidney and skeletal muscle were measured in 20 animals that received one bolus per 20 kg body wt. The results indicate that SMZ residues are cleared rapidly, and are at or below the tolerance level of 0.1 mg/kg within 8 days after dosing so that the 18-day withdrawal time used in cattle would provide an appropriate margin of safety if used in sheep.     

Pharmacokinetics and residues of a new oral amoxicillin formulation in piglets: a preliminary study

The pharmacokinetics of amoxicillin (Amx) were determined in pigs following intravenous (IV) administration of a single dose of 15 mg/kg and a single dose of 15 mg/kg of a new oral formulation (Amx-FP containing 10% amoxicillin). Residue studies were performed to determine residues in edible tissues of healthy pigs after chronic oral administration of Amx-FP at a daily dose of 15 mg/kg for five consecutive days. After IV administration, the plasma concentration was characteristic of a two-compartment open model. The main pharmacokinetic variables were: t(1/2lambda(n)), MRT=90.1 min, V(darea)=0.81 L/kg and Cl(b)=3.9 mL/kg/min. After single oral administration the main pharmacokinetic variables were: C(max)=758 mug/L, t(max)=347 min and Cl(b/f)=3.7 mL/kg/min for Amx-FP. The oral bioavailability (F) was calculated at 11% for Amx-FP. Based on maximum residue levels (MRL) for AMX in pigs established at 50 microg/kg for all tissues, the withdrawal times of AMX in muscle and skin plus fat were estimated (95% tolerance limit and 95% confidence) to fall below the MRL after a withdrawal period of seven days. Levels of AMX in the liver and kidneys were estimated to fall below the MRL after a withdrawal period of four days.     

Development of a physiologic-based pharmacokinetic model for estimating sulfamethazine concentrations in swine and application to prediction of violative residues in edible tissues

OBJECTIVE: To develop a flow-limited, physiologic-based pharmacokinetic model for use in estimating concentrations of sulfamethazine after IV administration to swine. SAMPLE POPULATION: 4 published studies provided physiologic values for organ weights, blood flows, clearance, and tissue-to-blood partition coefficients, and 3 published studies provided data on plasma and other tissue compartments for model validation. PROCEDURE: For the parent compound, the model included compartments for blood, adipose, muscle, liver, and kidney tissue with an extra compartment representing the remaining carcass. Compartments for the N-acetyl metabolite included the liver and the remaining body. The model was created and optimized by use of computer software. Sensitivity analysis was completed to evaluate the importance of each constant on the whole model. The model was validated and used to estimate a withhold interval after an IV injection at a dose of 50 mg/kg. The withhold interval was compared to the interval estimated by the Food Animal Residue Avoidance Databank (FARAD). RESULTS: Specific tissue correlations for plasma, adipose, muscle, kidney, and liver tissue compartments were 0.93, 0.86, 0.99, 0.94, and 0.98, respectively. The model typically overpredicted concentrations at early time points but had excellent accuracy at later time points. The withhold interval estimated by use of the model was 120 hours, compared with 100 hours estimated by FARAD. CONCLUSIONS AND CLINICAL RELEVANCE: Use of this model enabled accurate prediction of sulfamethazine pharmacokinetics in swine and has applications for food safety and prediction of drug residues in edible tissues.     

Disposition kinetics of doxycycline in chickens naturally infected with Mycoplasma gallisepticum

1. The pharmacokinetic properties of doxycycline were determined in healthy chickens and chickens naturally infected with Mycoplasma gallisepticum after a single intravenous (i.v.) and oral administration of the drug at 20 mg/kg body weight. Tissue residues of the tested drug after an oral dose of 20 mg/kg given twice daily for 5 consecutive days were also estimated in diseased chickens. 2. The plasma concentrations of doxycycline following single i.v. and oral administration were higher in healthy chickens than in diseased ones. Following i.v. injection, the elimination half-life (t1/2beta), distribution half-life and mean residence time (MRT) were longer in healthy chickens than in diseased birds. The values of total body clearance (ClB) and volume of distribution (Vdss) were larger in healthy chickens than in diseased birds. 3. After single oral administration, the absorption half-life (tl/2ab) and the elimination half-life were longer in normal birds than in diseased ones. The maximum plasma concentration of the drug was higher in normal chickens than in diseased ones. 4. Following repeated oral administration, the concentration of doxycycline in all tissues except muscle was higher than the corresponding concentrations in plasma. Concentrations of doxycycline in different tissues were in the following order: kidney > liver > lung > muscle. The drug was detected in liver and kidney in substantial concentrations on d 5 post administration of the last dose whereas, on d 7, its concentration in all tissues was below the lower limit of the sensitivity of the assay method used. Because of the low sensitivity of the microbiological assay method used in this study, a safe withdrawal time for doxycycline in diseased birds could not be estimated for the meanwhile.     

Isometamidium in goats: disposition kinetics, mammary excretion and tissue residues

The pharmacokinetics of the antitrypanosomal drug isometamidium were studied in lactating goats after intravenous and intramuscular administration at a dose of 0.5 mg/kg body weight, in a crossover design at an interval of 6 weeks. Following intravenous administration, the half-life of the disappearance of the drug from plasma during the terminal phase was 3.2 h, and the mean residence time was 2.4 h. The apparent volume of distribution averaged 1.52 l/kg, and the mean total body clearance was 0.308 l/kg/h. After intramuscular administration, the absolute bioavailability was low, averaging 27%. This was consistent with a low mean maximum concentration of 24 ng/ml which occurred after 6 h. No drug was detectable (less than 10 ng/ml) in milk samples collected over a period of 14 days following drug administration by either the intravenous or intramuscular route. In tissues analysed when the goats were killed 6 weeks after administration of the second dose, no drug was detectable (less than 0.4 micrograms/g wet tissue) in the liver, kidney and muscle. However, at the injection site, drug concentrations varied from less than 0.4 to 18.8 micrograms/g wet tissue.     

Oxytetracycline pharmacokinetics, tissue depletion, and toxicity after administration of a long-acting preparation at double the label dosage

Oxytetracycline (OTC) concentration in plasma and tissues, plasma pharmacokinetics, depletion from tissue, and toxicity were studied in 30 healthy calves after IM administration of a long-acting OTC preparation (40 mg/kg of body weight) at double the label dosage (20 mg/kg). Plasma OTC concentration increased rapidly after drug administration, and by 2 hours, mean (+/- SD) values were 7.4 +/- 2.6 micrograms/ml, Peak plasma OTC concentration was 9.6 +/- 2.6 micrograms/ml, and the time to peak plasma concentration was 7.6 +/- 4.0 hours. Plasma OTC concentration decreased slowly for 168 hours (elimination phase) after drug administration, and the elimination half-life was 23.9 hours. Plasma OTC concentration exceeded 3.8 micrograms/ml at 48 hours after drug administration. From 168 to 240 hours after drug administration, plasma OTC concentration decreased at a slower rate than that seen during the elimination phase. This slower phase was termed the depletion phase, and the depletion half-life was 280.7 hours. Tissue OTC concentration was highest in kidneys and liver. Lung OTC concentration exceeded 4.4 micrograms/g of tissue and 2.0 micrograms/g of tissue at 12 and 48 hours after drug administration, respectively. The drug persisted the longest in kidneys and liver. At 42 days after drug administration, 0.1 micrograms of OTC/g of kidney was detected. At 49 days after drug administration, all OTC tissue concentrations were below the detectable limit. Reactions and toxicosis after drug administration were limited to an anaphylaxis-like reaction (n = 1) and injection site swellings (n = 2).     

Chloramphenicol concentrations in calf muscle tissue

Twenty-five 9- to 11-week-old calves were administered 2 doses of chloramphenicol prepared in propylene glycol (13.6 mg/kg of body weight IV; 6.8 mg/kg IM; or 13.6 mg/kg IM) at 24-hour intervals. Calves were euthanatized at designated times from 2 to 72 hours after the last dose was administered. Muscle tissues were collected immediately after euthanasia, and chloramphenicol concentrations in the tissues were determined.     

磺胺二甲嘧啶在黑鲪体内的药物代谢动力学和残留消除研究

在(14±1)℃水温条件下,对黑鲪单次口灌100 mg/kg体重的磺胺二甲嘧啶,进行药物代谢动力学研究。在(20±2)℃水温条件下,按照《中华人民共和国水产行业标准磺胺类药物水产养殖使用规范》推荐剂量对黑鮶连续5天口灌给予磺胺二甲嘧啶,研究其在黑鮶体内的残留消除规律。血浆、肌肉和肝脏样品采用高效液相色谱检测,DAS2.0药物代谢动力学软件对数据进行处理分析。结果表明磺胺二甲嘧啶在黑鲪血浆、肌肉和肝脏中均符合一室模型,肝脏、血液和肌肉中药物达峰时间分别为6 h,8 h和10 h;峰值浓度分别为26.45μg/g、25.57μg/g和31.15μg/g;连续多次给药后,黑鮶血液、肌肉、肝脏中药物浓度分别在给药后12d、14d、15d后小于最大残留限量要求(0.1mg/kg)。     

Tissue disposition and depletion of penicillin G after oral administration with milk in unweaned dairy calves

OBJECTIVE: To determine tissue depletion of penicillin G in calves after oral ingestion with milk replacer and estimate a withdrawal period. DESIGN: Longitudinal controlled trial. ANIMALS: 26 Holstein calves. PROCEDURE: Once daily, 24 calves were fed milk replacer containing procaine penicillin G (0.68 mg/kg [0.31 mg/lb] of body weight); 2 calves served as controls. After 1 feeding, 12 calves were euthanatized in groups of 3 each 4, 6.5, 9.5, and 13 hours after feeding. After 14 days, 12 calves were euthanatized in groups of 3 each 4, 6.5, 9.5, and 13 hours after the final feeding. Concentrations of penicillin G were determined in tissues, blood, and urine by use of high-performance liquid chromatography. RESULTS: Penicillin G was not detected in muscle samples of treated calves. The highest concentrations of penicillin G in plasma, kidney, and liver were 13 ng/ml, 92 ng/g, and 142 ng/g, respectively. Thirteen carcasses had violative drug residues; 12 had violative residues in the liver only, and 1 had violative residues in the liver and kidney. A 21-hour withdrawal period was estimated. CONCLUSIONS AND CLINICAL RELEVANCE: Liver had the highest concentration of penicillin G and was most likely to have violative residues. Feeding calves milk containing penicillin G has the potential to cause violative drug residues in tissues. It is recommended to observe an appropriate withdrawal time prior to slaughter if calves are fed milk from cows treated with penicillin G.     

Tissue concentrations and pharmacokinetics of florfenicol in male veal calves given repeated doses

The pharmacokinetic disposition of florfenicol was studied in male veal calves given 11 mg of florfenicol/kg of body weight, IV and 11 mg of florfenicol/kg PO every 12 hours for 7 doses. After florfenicol administration IV, the median elimination half-life was 222.8 minutes, whereas the median half-life of the distribution phase was 7.94 minutes. Median body clearance and apparent volume of distribution were 2.87 ml/kg/min and 0.907 L/kg, respectively. After florfenicol administration, PO, there was a wide variation in the calculated half-life, which was attributed to variation in the rate of florfenicol absorption. The half-life was 167.4 to 534.9 minutes after the first oral dose and 190 to 808.8 minutes after the seventh dose. The median bioavailability after the first oral dose was 0.8888. Peak and trough concentrations of florfenicol were increased after subsequent doses were administered, compared with those after the first oral dose. The percentage of protein binding in serum from one adult cow was 22% to 26%. Florfenicol concentrations in tissues and body fluids of male veal calves were studied after the seventh dose of 11 mg of florfenicol/kg. High concentrations of florfenicol were measured in the urine, kidney, and bile. Low concentrations were measured in the brain, CSF, and aqueous humor. Concentrations in all other tissues and fluids studied were similar to the concurrent serum concentration.     

Pharmacokinetic profile and tissue distribution of monensin in broiler chickens

1. The pharmacokinetics of monensin, including half‐life, apparent volume of distribution, total body clearance, systemic bio‐availability and tissue residues were determined in broiler chickens. The drug was given by intracrop and intravenous routes in a single dose of 40 mg/kg body weight.

2. Following intravenous injection the kinetic disposition of monensin followed a two compartments open model with absorption half life of 0.59 h, volume of distribution of 4.11 I/kg and total body clearance of 28.36 ml/kg/min. The highest serum concentrations of monensin were reached 0.5 h after intracrop dosage with an absorption half‐life of 0.27 h and an elimination half life of 2.11 h. The systemic bioavailability was 65.1% after intracorp administration. Serum protein‐binding tendency of monensin calculated in vitro was 22.8%.

3. Monensin concentrations in the serum and tissues of chickens after a single intracrop dose of pure monensin (40 mg/kg body weight) were higher than those after feeding a supplemented monensin pre‐mix (120 mg/kg) for 2 weeks. Monensin residues were detected in tested body tissues, collected 2, 4, 6 and 8 h after oral administration. The highest conentration was found in the liver. In addition, monensin residues were detected only in liver, kidney and fat 24 h after the last oral dose. No monensin residues could be detected in tissues after 48 h, except in liver which cleared completely by 72 h.     

Sulfamethazine residues in uncooked edible tissues of port following recommended oral administration and withdrawal.

Commercial feed rations containing sulfamethazine at the level of 110 ppm were fed for a period of 65 days to market pigs in a study simulating normal farm practices. The levels of sulfamethazine at the end of medication were in excess of 10 ppm in liver and kidney and up to 2.6 ppm in muscle tissues. Concentrations of sulfamethazine in tissues from pigs after withdrawal of medicated feed depleted to 0.1 ppm within nine days. The rate of depletion was similar for all tissues. It was observed that storage of tissue samples at freezer temperature (-20 degrees C) for 30 days further reduces sulfamethazine levels by 3 to 20% of their original value.