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.     

Plasma/muscle ratios of sulfadimethoxine residues in channel catfish (Ictalurus punctatus)

Channel catfish ( n = 84) maintained at a water temperature of 27°C were used in a feeding study to determine the plasma to muscle concentration ratios of sulfadimethoxine (SDM) and 4-N-acetylsulfadimethoxine residues. Sulfadimethoxine medicated feed was provided free choice at 42 mg SDM/kg body weight once daily for 5 days and the plasma and muscle concentrations of SDM were determined at selected withdrawal times (6, 12, 24, 48, 72, and 96 hours) following the last dose. Considerable variation in total SDM tissue concentration among fish within a sampling period was observed. For fish ( n = 12) at six hours post-dose, total SDM concentrations ranged from 1.4–24.8 μg/mL and 0.6–12.6 μg/g, with mean total SDM concentrations of 9.1 μg/mL and 5.3 μg/g for plasma and muscle, respectively. However, a mean plasma:muscle concentration ratio of 1.8:1 ± 0.3:1 was obtained over all concentrations and sampling periods. The plasma:muscle 95% t distribution interval for individual fish was 1.2:1 to 2.4:1. A correlation coefficient of 0.967 was obtained for the relationship between plasma and muscle total SDM concentration among individual fish ( n = 25). Results of this study indicate that plasma total SDM concentration may be used to identify samples containing violative SDM muscle residue. No fish contained total SDM muscle residues greater than the FDA tolerance (0.1 μg/g) by 48 hours following the final dose.     

USDA regulation of residues in meat and poultry products

The National Residue Program conducted by the Food Safety and Inspection Service (FSIS) of the USDA includes a comprehensive testing program for residues of pesticides, drugs and other chemical contaminants in meat and poultry. Prevention strategies encourage producers to adopt quality control measures in their production management to prevent illegal residues in food. These activities have been effective in reducing the occurrence of violative residues and the potential for adverse health effects. Overall, the number of domestic monitoring samples containing violative residues is low-about 1% of samples tested. Violative residues are found less frequently in poultry than in livestock. More occur in swine than in other species; the least number occur in fed cattle and broilers. Testing results over the last 10 yr show that most drugs and pesticides used to enhance agricultural productivity are not causing a residue problem in meat and poultry. However, the FSIS cannot be complacent about its program achievements. Unacceptably high incidences of violative residues of certain drugs, namely, sulfonamides and antibiotics, still occur in particular production classes. For example, the incidence of violative sulfonamide residues in liver samples from swine slaughtered in 1985 was about 6%, with significant differences between geographical areas. An estimated 2.5% of market hogs had violative sulfamethazine residues in the muscle tissue. The FSIS is taking steps to correct this and other residue problems by strengthening the link between residue detection and enforcement and by expanding its analytical capability to monitor for residues.     

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.     

Comparative pharmacokinetics of sulfamethazine in plasma and parotid saliva of sheep

Salivary output in sheep is large enough to be considered a physiologic body fluid compartment. The hypothesis for this work was that pharmacokinetics of sulfamethazine in saliva was similar to that in plasma. A reliable technique was developed to measure parotid salivary output. Mean output of saliva was 3.18 ± 1.04 L from a single parotid gland per day with a mean flow of 2.21 ± 0.43 mL/min. Using concentrations of sulfamethazine in parotid saliva made it possible to calculate the total passage of sulfamethazine to parotid saliva, which was calculated to be 3.5% of the total dose. Pharmacokinetic variables obtained for sulfamethazine in plasma and in saliva were closely related ( AUC 1408 μg.h/mL and AUC 1484 μg.h/mL; V d_area 0.434 L/kg and V d _area 0.374 L/kg; t _½β 4.30 h and 3.46 h, respectively) and no substantial differences were observed. The convenience of using salivary concentrations of sulfamethazine for drug monitoring is discussed.     

Sulfamethazine residues in swine: comparison of on-farm monitoring methods

Three sulfamethazine-residue detection methods were used to evaluate samples collected from five swine farms over a 12-month period. All cooperating farms included sulfamethazine in swine diets at various stages of production, for growth promotion or disease control, and followed recommended drug withdrawal periods. Swine finishing ration, swine urine, and swine serum from market-weight animals were tested monthly for the presence of sulfamethazine. Thin-layer chromatograph (TLC) analysis of swine urine was the gold standard by which three other test method-sample combinations were compared. Samples were analyzed for sulfamethazine using TLC (feed), competitive enzyme immunoassay (serum), and agar-diffusion swab test (urine). The relative sensitivities and specificities of sulfamethazine-residue detection for the three combinations were: (1) TLC analysis (27%, 94%); (2) competitive enzyme immunoassay analysis (58%, 59%); (3) agar-diffusion swab test (78%, 12%). None of the three methods tested was individually adequate for on-farm monitoring of sulfonamide residues. Sulfamethazine residues in swine urine were found on 43.3% of the monthly farm visits and in 19.7% of all swine tested.     

Pharmacokinetics of sulfamethazine in male, female and castrated male swine

The concentration of sulfamethazine in plasma and sulfamethazine and its metabolites in urine were compared in male, female and castrated male swine. A surgical technique for placement of catheters in the urinary bladder was used to facilitate the collection of urine in males and castrated males. The elimination rate of sulfamethazine from plasma and the excretion of parent drug and metabolites into urine did not differ significantly among females, males and castrated male swine.     

Occurrence of sulfa drug residues in canadian pork liver

Sulfonamide residues in the livers of wholesome carcasses of Canadian pork were monitored over the six year period ending March 31, 1985. The annual rate of violative residues decreased from 9.92% to 2.75% over the course of the six years. At present the incidence of violation in the livers is 2.35% and there is no significant difference within the various regions of Canada. This would result in a muscle violative rate of 0.8%.

The only sulfonamide found at violative levels was sulfamethazine. All violative samples were within the range 0.11-4.00 ppm. Over the period of the survey the incidence of violations at all levels decreased. Violations at higher levels decreased most rapidly resulting in a continuous reduction of the mean level in violative samples.

     

A physiologically based pharmacokinetic model linking plasma protein binding interactions with drug disposition

Combination drug therapy increases the chance for an adverse drug reactions due to drug-drug interactions. Altered disposition for sulfamethazine (SMZ) when concurrently administered with flunixin meglumine (FLU) in swine could lead to increased tissue residues. There is a need for a pharmacokinetic modeling technique that can predict the consequences of possible drug interactions. A physiologically based pharmacokinetic model was developed that links plasma protein binding interactions to drug disposition for SMZ and FLU in swine. The model predicted a sustained decrease in total drug and a temporary increase in free drug concentration. An in vivo study confirmed the presence of a drug interaction. Neither the model nor the in vivo study revealed clinically significant changes that alter tissue disposition. This novel linkage approach has use in the prediction of the clinical impact of plasma protein binding interactions. Ultimately it could be used in the design of dosing regimens and in the protection of the food supply through prediction and minimization of tissue residues.     

Water medication of a swine herd with amoxycillin

A swine herd, consisting of 201 swine, was treated with amoxycillin. Amoxycillin was administered in the water system for 5 days, at a mean dose of 23 mg/kg body weight per day. Twice a day the water consumption was monitored, and blood samples collected from 10 randomly selected pigs. The plasma concentration of amoxycillin was measured by use of high performance liquid chromatography (HPLC). Three days after initiating amoxycillin treatment, the plasma concentration reached a constant level, at which it varied between a maximum of 1.3 μg/mL and a minimum of 0.5 μg/mL. The plasma concentration was compared with a predicted curve based on pharmacokinetic variables obtained previously. The plasma concentrations were at the same level as the simulated ones. The minimum inhibitory concentration (MIC) values of the common respiratory pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida are about 0.1 μg/mL. In pigs the distribution between bronchial mucosa and plasma ( AUC _mucosa/ AUC _plasma) is 0.3, which indicates a therapeutic plasma concentration of 0.3 μg/mL. Data from the present study indicates that water medication with amoxycillin is effective as follow-up treatment.     

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.     

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.     

Persistence of transferable drug resistance in the lactose-fermenting enteric flora of swine following antimicrobial feeding.

Six groups of swine (85 animals) were fed a combination of antimicrobial drugs (sulfamethazine 100 g/ton, chlortetracycline 100 g/ton and penicillin 50 g/ton). After two weeks the antimicronial drugs were removed from the diet of two groups (28 animals). These swine were compared to four groups fed the medicated diet to determine the effect of duration of treatment and degree of animal isolation on the persistence of resistance in lactose-fermenting enteric organisms. The degree of resistance to penicillin, oxytetracycline, dihydrostreptomycin and neomycin as determined by minimum inhibitory concentrations and the incidence of resistant organisms were examined during and after antibiotic feedings. Ninety-two percent or greater of all isolates tested during and after treatment had minimum inhibitory concentrations for oxytetracycline of greater than 100 mug/ml. Thirty-two weeks after cessation of dietary antibiotic, resistance to oxytetracycline and dihydrostreptomycin remained at 100% and 89% respectively. Variation in degree of contact between swine receiving medicated feed and those receiving nonmedicated feed was not sufficient to reduce the incidence of resistance to oxytetracycline or dihydrostreptomycin in all animals. Factors influencing persistence of resistant enteric organisms are discussed. Addition of the antimicrobials to the ration resulted in significantly greater weight gains for treated animals than for the controls but did not alter feed conversion.     

Chronic exposure to the mycotoxin T‐2 promotes oral absorption of chlortetracycline in pigs

The aim of this study was to investigate whether T‐2 toxin, a potent Fusarium mycotoxin, affects the oral absorption of the antibiotic chlortetracycline in pigs. Animals were allocated to blank feed without T‐2 toxin (controls), feed containing 111 μg T‐2/kg feed, T‐2‐contaminated feed supplemented with a yeast‐derived feed additive, or blank feed supplemented solely with the feed additive, respectively. After 21 days, an intragastric bolus of chlortetracycline was given to assess potential alterations in the pharmacokinetics of this commonly used antibiotic. A significantly higher area under the plasma concentration–time curve and maximal plasma concentration of chlortetracycline was observed after intake of T‐2‐contaminated feed compared with control. Thus, exposure to T‐2‐contaminated feed can influence the oral bioavailability of chlortetracycline. This effect could have consequences for the withdrawal time of the drug and the occurrence of undesirable residues in edible tissues.     

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.     

The disposition of suxibuzone in the horse

A high performance liquid chromatographic method is described to determine the anti-inflammatory drug suxibuzone (SXB) and its major metabolites phenylbutazone (PBZ) and oxyphenbutazone (OPBZ) in equine plasma and urine. When suxibuzone (6 mg/kg) was administered intravenously (i.v.) or orally (p.o.) no parent drug was detected in plasma or in urine. The disposition of the metabolite PBZ (i.v.) could be described by a 2 compartment model with a P half-life varying from 7.40 to 8.35 h. Due to severe side effects the use of i.v. suxibuzone should not be encouraged in the horse. PBZ and OPBZ were detected in plasma and urine after p.o. SXB administration. Peak plasma PBZ concentrations (8.8 ± 3.0 μg/ml) occurred 6 h after oral dosing and the terminal exponential constant was 0.11 ± 0.01 h^-1. Phenylbutazone and oxyphenbutazone were detectable in urine (> 1 μg/ml) for at least 36 h, after p.o. administration.
SXB was not hydrolyzed in vitro by horse plasma. Equine liver homogenates however appeared to have a very high capacity for hydrolysing SXB, indicating that first-pass effect could be responsible for the rapid disappearance of this NSAID in the horse.     

Chemical composition, digestibility, and voluntary feed intake of mango residues by sheep

The chemical composition, digestibility, and voluntary feed intake by sheep of mango by-products were studied in an experiment with five dietary treatments consisting of mango peels and seed kernels, offered individually or together with urea block and a control. The mango residues were offered with rice straw and the control diet was straw only. Five groups of five male sheep of Djallonké type, 12–18 months old and weighing on average 18.6 kg were allocated randomly to the diets to assess the voluntary feed intake. Apparent digestibility of the same diets was measured using four sheep per diet. The mango residues were low in crude protein, 67 and 70 g/kg dry matter for the peels and the seed kernels, respectively. The content of neutral detergent fiber varied from 306 to 388 g/kg dry matter (DM) for the kernel and the peels, respectively. The kernel had relatively high level of fat (105 g/kg DM) and tannins (29 and 40 g/kg DM of hydrolysable and total tannins, respectively). The highest intake was observed with the diet containing both residues and urea block (741 g/day). The intake of kernels was lower in all diets when offered with the peels than when offered with rice straw alone. Apparent digestibility of the diets containing mango residues was 0.60–0.65. The peels and kernels had high digestibility coefficients (0.74 and 0.70, respectively). Based on the results above, it can be concluded that it would be interesting to test the residues in a growth experiment.     

Concentration of enrofloxacin and its active metabolite in alveolar macrophages and pulmonary epithelial lining fluid of dogs

The purpose of this study was to determine the concentration of enrofloxacin and its active metabolite, ciprofloxacin, in alveolar macrophages (AM) and epithelial lining fluid (ELF) of the lungs in comparison to plasma concentrations in healthy dogs. Eleven dogs were given a single oral dose (5 mg/kg) of enrofloxacin. Four hours later, plasma and bronchoalveolar lavage (BAL) fluid were collected. Cells were separated from the BAL fluid and lysed for determination of drug concentrations within AM. Supernatant was used to determine concentrations of drugs in ELF. Drug assays were performed by high-performance liquid chromatography.
  The concentration of enrofloxacin (mean ± SD) was 0.33 ± 0.14 μg/mL in plasma, 3.34 ± 2.4 μg/mL in AM and 4.79 ± 5.0 μg/mL in ELF. The concentration of ciprofloxacin was 0.42 ± 0.26 μg/mL in plasma, 1.15 ± 1.03 μg/mL in AM and 0.26 ± 0.26 μg/mL in ELF. Mean concentrations of both drugs in AM were greater than in plasma (AM to plasma ratio, 10.3 for enrofloxacin and 4.7 for ciprofloxacin). Mean concentrations of enrofloxacin, but not ciprofloxacin, in ELF were greater than in plasma (ELF to plasma ratio, 13.5 for enrofloxacin and 0.52 for ciprofloxacin). Enrofloxacin concentrations in AM and ELF largely exceeded the MICs of the major bacterial pathogens and surpassed by about two times the breakpoint MIC of that drug, and ciprofloxacin concentrations in AM surpassed the MIC of many susceptible organisms. These results suggest that sufficient antimicrobial activity is present in AM and ELF of dogs following oral administration of enrofloxacin to be effective in the treatment of lower respiratory tract infections involving susceptible organisms.     

Factors that affect drug disposition in food-producing animals during maturation.

Drugs administered to neonatal food-producing animals (cattle, sheep, goats, swine) may exhibit significantly different pharmacokinetic/disposition characteristics than they do in adult animals of the same species. Undesirable consequences such as suboptimum therapeutic concentrations, toxic effects, and violative tissue residues may result if adult dosage regimens are employed in young animals. Using selected drugs as examples, this paper reviews factors that contribute to differences in drug disposition in newborn vs adult animals. Immaturity of mechanisms involved in drug absorption, especially from gastrointestinal and parenteral sites of administration, and of drug distribution to sites such as plasma proteins, adipose tissue, and fluid compartments are considered. The role of developmental changes in drug biotransformation in the liver and other tissues and the maturation of excretory mechanisms, primarily from the kidney, in the increased rate of drug clearance during maturation is described. Pharmacokinetic studies with specific drugs in the target species are an important approach to establishing rational drug use in immature food-producing animals.     

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。