Depletion of dietary sulphamonomethoxine and sulphadimethoxine from various tissues of laying hens

1. Sulphamonomethoxine (SMM) or sulphadimethoxine (SDM) was fed to laying hens at 400 mg/kg diet for 5 successive days. After withdrawal of the drugs, contents (mg/kg) of SMM and SDM in the blood, kidney, liver, ovary, muscle and adipose tissue were determined by HPLC.

2. The disappearance of dietary SMM and SDM from the tissues of laying hens was rapid and, except for the liver, was very similar in all tissues.

3. A common biological half‐life (t.fr1/2>) of SMM in the above 6 tissues was estimated to be 5.2 h. The t.fr1/2> of SDM in the liver was 6.9 h, significantly longer than that of 4.4 h in the other 5 tissues. The values were much shorter than t.fr1/2> (reported elsewhere) for other drugs.

4. Comparing the data found in this study with those obtained from previous papers, the depletion velocities of SMM and SDM from the hen's body were much faster than those from albumen in egg. The reason for this is probably related to the longer time period over which albumen formation occurs.     

In vitro hepatobiotransformation of sulphadimethoxine in laying hens

The biotransformation of sulphadimethoxine (SDM) was estimated in liver post-mitochondrial supernatants (S-9) from laying hens. The pathway and activity for hen S-9 were compared with those for cow and pig S-9. The formation of the hydroxylation of SDM, 6-hydroxy SDM (6-OH-SDM), was found only with hen S-9. The N4-acetylating activity of SDM in hen S-9 was lower than in cow and pig S-9. All S-9 from the three species de-acetylated N4-acetyl SDM (N4-AcSDM). With respect to the hydroxylation and N4-acetylation rates in hen S-9, the values incubated at 41 degrees C were higher than those at 37 degrees C (P < 0.01).     

Transfer of dietary sulphamonomethoxine and sulphadimethoxine into various tissues of laying hens

1. Sulphamonomethoxine (SMM) or sulphadimethoxine (SDM) were fed to laying hens at a dietary concentration of 400 mg/kg. Concentrations (mg/kg) of SMM and SDM in the blood, kidney, liver, ovary, muscle and adipose tissue, collected at 4, 8, 16 and 24 h after the start of feeding, were determined by HPLC

2. The relationships between the sulphonamide concentrations (mg/kg) in the tissues and times (h) after the start of the feeding were analysed statistically.

3. Dietary SMM and SDM were transferred throughout the whole body, and concentrations in all tissues became constant 8 h after the start of feeding.

4. Among the 6 tissues examined the constant values (mg/kg) of both SMM and SDM were highest in the kidney and were lowest in adipose tissue.

5. With the exception of adipose tissue, the values of SDM in the tissues were statistically greater than those of SMM.     

Pharmacokinetics, renal clearance, tissue distribution, and residue aspects of sulphadimidine and its N4-acetyl metabolite in pigs

Pharmacokinetics and tissue distribution experiments were conducted in pigs to which sulphadimidine (SDM) was administered intravenously, orally, and intramuscularly at a dosage of 20 mg SDM/kg. SDM was acetylated extensively, but neither hydroxy metabolites nor their derivatives could be detected in plasma, edible tissues or urine. Following i.v. and two oral routes of administration, the N4-acetylsulphadimidine (N4-SDM) concentration-time curve runs parallel to that of SDM. The percentage of N4-SDM in plasma was in the range between 7 and 13.5% of the total sulphonamide concentration. The bioavailability of SDM administered in a drench was 88.9 +/- 5.4% and administered mixed with pelleted feed for 3 consecutive days it was 48.0 +/- 11.5%. The renal clearance of unbound SDM, which was urine flow related, was 1/7 of that of creatinine, indicating reabsorption of the parent drug. The unbound N4-SDM was eliminated three times faster than creatinine, indicating that tubular secretion was the predominant mechanism of excretion. After i.v. administration, 51.9% of the administered dose was recovered in urine within 72 h p.i., one quarter of which as SDM and three quarters as N4-SDM. Tissue distribution data obtained at 26, 74, 168, and 218 h after i.m. injection revealed that the highest SDM concentration was found in plasma. The SDM concentration in muscle, liver, and kidney ranged from one third to one fifth of that in plasma. The N4-SDM formed a minor part of the sulphonamide content in edible tissues, in which the SDM as well as the N4-SDM concentration parallelled the plasma concentrations. Negative results obtained with a semi-quantitative bioassay method, based on monitoring of urine or plasma, revealed that the SDM concentration levels in edible tissues were in that case below 0.1 mu/g tissue.     

Tissue concentrations of sulphaquinoxaline administered in the food of laying hens

1. Sulphaquinoxaline (SQ) was fed to laying hens at a dietary level of 400 mg/kg for 3 successive days. SQ contents (mg/kg) in the blood, kidney, liver, ovary, muscle (thigh) and adipose tissue collected on 1, 2, and 3 d after the start of feeding were determined by HPLC. The relationship between the SQ content in the tissues and times (d) of SQ feeding was analyzed statistically. 2. Dietary SQ was distributed throughout the whole body. 3. Contents in tissues, except the kidney, had already reached a plateau by day 1 after the start of administration whereas in the kidney it increased linearly throughout the 3 days. 4. The plateau values of SQ in the tissues were much greater than those of sulphamonomethoxine and sulphadimethoxine.     

Molecular cloning and tissue expression of chicken AdipoR1 and AdipoR2 complementary deoxyribonucleic acids

AdipoR1 and AdipoR2 belong to a novel class of transmembrane receptors that mediate the effects of adiponectin. We have cloned the chicken AdipoR1 and AdipoR2 complementary deoxyribonucleic acids (cDNA) and determined their expression in various tissues. We also investigated the effect of feed deprivation on the expression of AdipoR1 or AdipoR2 mRNA in the chicken diencephalon, liver, anterior pituitary gland, and adipose tissue. The chicken AdipoR1 and AdipoR2 cDNA sequences were 76-83% identical to the respective mammalian sequences. A hydrophobicity analysis of the deduced amino acid sequences of chicken AdipoR1/AdipoR2 revealed seven distinct hydrophobic regions representing seven transmembrane domains. By RT-PCR, we detected AdipoR1 and AdipoR2 mRNA in adipose tissue, liver, anterior pituitary gland, diencephalon, skeletal muscle, kidney, spleen, ovary, and blood. AdipoR1 or AdipoR2 mRNA expression in various tissues was quantified by real-time quantitative PCR, and AdipoR1 mRNA expression was the highest in skeletal muscle, adipose tissue and diencephalon, followed by kidney, ovary, liver, anterior pituitary gland, and spleen. AdipoR2 mRNA expression was the highest in adipose tissue followed by skeletal muscle, liver, ovary, diencephalon, anterior pituitary gland, kidney, and spleen. We also found that a 48 h feed deprivation significantly decreased AdipoR1 mRNA quantity in the chicken pituitary gland, while AdipoR2 mRNA quantity was significantly increased in adipose tissue (P<0.05). We conclude that the AdipoR1 and AdipoR2 genes are ubiquitously expressed in chicken tissues and that their expression is altered by feed deprivation in the anterior pituitary gland and adipose tissue.     

Plasma disposition and renal clearance of sulphadimidine and its metabolites in laying hens

Plasma disposition of sulphadimidine (SDM) and its metabolites was studied in laying hens after 100 mg SDM kg-1 doses were administered as a single intravenous dose, a single oral dose and multiple oral doses once daily for five consecutive days. SDM was extensively metabolised by acetylation and hydroxylation. In plasma, the metabolite observed with the highest concentration was N4-acetylsulphadimidine (N4-SDM) followed by hydroxymethylsulphadimidine (CH2OH) and 5-hydroxysulphadimidine. Following intravenous administration a biphasic elimination (as seen for a capacity limited reaction) pattern for SDM and its metabolites was observed. Multiple (5x) SDM dosing revealed plasma SDM concentrations ranging between 7 and 108 micrograms ml-1; within 96 hours of termination of the multiple SDM dosing, the plasma SDM concentration was below 0.01 micrograms ml-1. The renal clearances of N4-SDM and the hydroxy metabolites were approximately 10 times greater than that of SDM. The SDM mass balance (faecal/urinary recovery) showed a loss of 56 per cent after intravenous dosage and of 67 per cent after a single oral dosage; the hydroxy metabolites accounted for the highest percentage in faeces/urine. Thus additional metabolic pathways must exist in laying hens.     

Pharmacokinetics of sulfadimidine and its N4-acetyl metabolite in healthy and diseased rabbits infected with Pasteurella multocida

The pharmacokinetics of sulfadimidine (SDM) and its N4-acetyl metabolite (N4SDM) were investigated after intravenous bolus injection of a single dose (200 mg/kg) of SDM in normal and diseased New Zealand white rabbits. The apparent distribution volume at steady state, total body clearance and elimination half-life of SDM in normal animals were 0.7 +/- 0.3 l/kg, 0.57 +/- 0.24 l/kg/h and 1.6 +/- 1.3 h, respectively. Of the administered dose, 62.1% was metabolized by N4-acetylation, and 12.7 +/- 1.1 and 2.8 +/- 1.8% of the dose was excreted as free drug by the kidney and gastrointestinal tract, respectively. The 'apparent' formation and elimination half-lives of N4SDM were 0.6 +/- 0.4 and 2.2 +/- 1.1 h, respectively. The metabolite was eliminated mainly by excretion through the kidney. There was no significant effect of acute pasteurellosis on the pharmacokinetics of either SDM or N4SDM in rabbits.     

Pharmacokinetics,renal clearance,tissue distribution,and residue aspects of sulphadimidine and its N4‐acetyl metabolite in pigs

Summary

Pharmacokinetics and tissue distribution experiments were conducted in pigs to which sulphadimidine (SDM) was administered intravenously, orally, and intramuscularly at a dosage of 20 mg SDM/kg. SDM was acetylated extensively, but neither hydroxy metabolites nor their derivatives could be detected in plasma, edible tissues or urine. Following i.v. and two oral routes of administration, the N₄‐acetylsulphadimidine (N₄‐SDM) concentration‐time curve runs parallel to that of SDM. The percentage of N₄‐SDM in plasma was in the range between 7 and 13.5% of the total sulphonamide concentration. The bioavailability of SDM administered in a drench was 88.9 ± 5.4 % and administered mixed with pelleted feed for 3 consecutive days it was 48.0 ± 11.5 %. The renal clearance of unbound SDM, which was urine flow related, was 1/7 of that of creatinine, indicating reabsorption of the parent drug. The unbound N₄SDM was eliminated three times faster than creatinine, indicating that tubular secretion was the predominant mechanism of excretion.

After i.v. administration, 51.9 % of the administered dose was recovered in urine within 72 h p.i., one quarter of which as SDM and three quarters as N₄‐SDM.

Tissue distribution data obtained at 26, 74, 168, and 218 h after i.m. injection revealed that the highest SDM concentration was found in plasma. The SDM concentration in muscle, liver, and kidney ranged from one third to one fifth of that in plasma. The N₄‐SDM formed a minor part of the sulphonamide content in edible tissues, in which the SDM as well as the N₄‐SDM concentration parallelled the plasma concentrations.

Negative results obtained with a semi‐quantitative bioassay method, based on monitoring of urine or plasma, revealed that the SDM concentration levels in edible tissues were in that case below 0. 1μ/g tissue.     

Biliary elimination kinetics and tissue concentrations of oxytetracycline after intravenous administration in hens

The pharmacokinetics of the biliary elimination of oxytetracycline (OTC) and tissue concentrations in certain organs were studied in 10 Leghorn hens. The animals were anaesthetized using xylazine/ketamine administered by the intramuscular (i.m.) route and were immobilized for right laparotomy. Both bile ducts were cannulated and a dose of 20 mg/kg of oxytetracycline hydrochloride was administered intravenously (i.v.). Samples of bile excreted were taken at predetermined intervals during 6 h. At 6 h animals were slaughtered and tissue samples of blood, liver, kidney, pancreas, spleen, heart, lung and pectoral muscle were taken. The values for OTC biliary elimination rate times were best fitted to a one-exponential equation. The maximum value for OTC biliary excretion rate (3.69+/-0.6 microg/min/kg) was reached at approximately 17.5 min (time to maximum concentration (tmax)). The first-order rate constant for the biliary excretion (k) and the half-life (t1/2) were 6.7x10(-3) min(-1) and 110.55 min, respectively. The mean value of area under the biliary excretion rate time curve (AUC) indicated that 839.77 microg/kg body weight (b.w.) were eliminated by the biliary route. The cumulative biliary excretion data indicated that approximately 4.20% of the dose was eliminated by this route, 3.28% being eliminated during the first 6 h and 0.92% thereafter. The highest mean concentrations were found in the kidney (35.82 microg/kg) and liver (16.77 microg/g). Significant differences were found between the concentrations of the various tissues studied. Plasma concentration was lower than that of the other tissues (except lung).     

Accumulation of zinc in egg yolk, ovarian follicles and organs after forced resting by high dietary zinc

1. Eighteen Warren SSL hens of 71 weeks of age were forced-moulted by ad libitum feeding of a high-zinc diet (10,000 ppm zinc for 2 days followed by 5,000 ppm zinc-supplement diet for 4 days). From the start of the treatment, eggs were collected and 3 hens were slaughtered on days 0, 2, 3, 4, 5 and 6 of the study. 2. Zinc analyses were carried out on the different components of the eggs and on liver, pancreas, kidney, different yolky follicles of the ovary and various segments of the oviduct. 3. Seven-, six- and threefold increases in zinc concentration were found in pancreas, liver and kidney, respectively. 4. The shell gland and isthmus, but not the magnum, also showed slight but significant increases in Zn content. 5. Zinc accumulation was also high and almost identical in ovarian follicles F1 to F4 but slightly less in F5 and F6 follicles. 6. In the egg, a significant increase in zinc concentration was only observed in the yolk.     

Tissue/fluid correlation study for the depletion of sulfadimethoxine in bovine kidney, liver, plasma, urine, and oral fluid

Sulfonamides are among the oldest, but still effective, antimicrobial veterinary medicines. In steers and dairy cows, the sulfonamides are effective in the treatment of respiratory disease and general infections. Sulfadimethoxine (SDM) has been approved by US Food and Drug Administration (FDA) for use in steers and dairy cows with a tolerance of 100 ng/g (ppb) in edible tissues and 10 ppb in milk. The detection of SDM residue above tolerance in the animal slaughtered for food process will result in the whole carcass being discarded. This report describes a comprehensive depletion study of SDM (and its main metabolite) in plasma, urine, oral fluid, kidney, and liver. In this study, nine steers were injected intravenously with the approved dose of SDM; the loading dose was 55 mg/kg, followed by 27.5 mg/kg dose at 24 h and again at 48 h. Fluids (blood, urine, and saliva) and tissue (liver and kidney) samples were collected at intervals after the last dose of SMD. The combination of laparoscopic serial sampling technique with the liquid chromatography/mass spectrometry method provided the data to establish the tissue/fluid correlation in the depletion of SMD. A strong correlation and linearity of the log-scale concentration over time in the depletion stage has been confirmed for kidney, liver, and plasma.     

Sulfadimethoxine in giant freshwater prawns (Macrobrachium rosenbergii): an attempt to estimate the withdrawal time by a population pharmacokinetic approach

The fates of sulfadimethoxine (SDM) for different routes of administration were investigated in muscle tissue of giant freshwater prawns, Macrobrachium rosenbergii, following either intramuscular (i.m.) or gavage administration at a dosage of 50 mg/kg body weight (b.w.). The depletion patterns of SDM were also examined after medicated feed treatment at the feeding concentration of 10 g/kg of feed twice a day at a rate of 1% of total b.w. for five consecutive days. The concentration of SDM in prawn muscle tissue was measured using a high‐performance liquid chromatography (HPLC) equipped with ultraviolet detector. Noncompartmental analyses were used to estimate basic pharmacokinetic parameters for the i.m. and gavage data, while a population model was developed to analyze the entire data set including the feed group. Using the Monte Carlo simulations, the withdrawal times (WT) for the orally administered SDM in feed supplement were determined. Maximum concentration of SDM was significantly higher in the i.m. than in the gavage group, and the area under the curve (AUC) value for relative bioavailability following gavage administration was 25.6%. Using Monte Carlo simulation, for a maximum residue limit (MRL) of 0.1 μg/g, the WT for muscle after oral administration of SDM in feed was estimated to be 67 h, while for a MRL of 0.2 μg/g, the WT was estimated to be of 54 h.     

Polluting profiles of dieldrin and DDTs in laying hens of Osaka, Japan

Contaminating/accumulating levels of organochlorine pesticides in extractable fats from a basal diet, eggs and seven tissues (adipose tissue, blood, kidney, liver, muscle, ovary and oviduct) and excreta of laying hens that were kept in a general poultry farm of Japan were examined. No benzene hexachlorides or aldrin was detected [< 1 part per billion (p.p.b.)] overall. Dieldrin and all DDTs (p,p'-DDE, o,p'-DDT, p,p'-DDD and p,p'-DDT) were contaminated in the dietary fats (mean range 10-70 p.p.b.). Although dieldrin (4-58 p.p.b.), p,p'-DDE (65-196 p.p.b.) and p,p'-DDT (30-73 p.p.b.) were found to be accumulated in all the tissue fats and egg yolk fats, they were not detected in the dried excreta. Accumulations of o,p'-DDT and p,p'-DDD were found only in the liver fat (92 p.p.b.) and in the kidney fat (27 p.p.b.), respectively. In all the samples, p,p'-DDE levels were highest in comparison with the other compounds. For all organochlorine pesticides detected, the accumulated levels were well below the practical residue limits.     

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.     

Lead contamination of chicken eggs and tissues from a small farm flock.

Twenty mixed-breed adult laying hens from a small farm flock in Iowa were clinically normal but had been exposed to chips of lead-based paint in their environment. These chickens were brought to the Iowa State University Veterinary Diagnostic Laboratory, Ames, Iowa, where the concentration of lead in blood, eggs (yolk, albumen, and shell), and tissues (liver, kidney, muscle, and ovary) from 5 selected chickens was determined over a period of 9 days. Blood lead levels ranged from less than 50 to 760 ppb. Lead contamination of the yolks varied from less than 20 to 400 ppb, and shells were found to contain up to 450 ppb lead. Albumen contained no detectable amount. Lead content of the egg yolks strongly correlated with blood lead levels. Deposition of lead in the shells did not correlate well with blood lead levels. Mean tissue lead accumulation was highest in kidneys (1,360 ppb), with livers ranking second (500 ppb) and ovarian tissue third (320 ppb). Muscle contained the lowest level of lead (280 ppb). Lead contamination of egg yolks and edible chicken tissues represents a potential public health hazard, especially to children repeatedly consuming eggs from contaminated family-owned flocks.     

Distribution of 15N-chlorocholine chloride in eggs of laying hens

The distribution of Chlorocholine chloride (CCC) in the eggs of laying hens was studied using 15N-CCC. Twelve layers (37 weeks old) were divided into four groups and used in this study consisting of three feeding phases. In phase one (7 days), all the hens received a CCC-free diet [165 g CP/kg dry matter (DM); 11.58 MJ ME/kg DM]. In phase two (11 days), four levels of 15N-CCC: 0, 5, 50 and 250 ppm were added to the respective diets, while in phase three (7 days), CCC-free feed was again offered. Egg samples were taken and the 15N content of egg yolk and albumin were determined. At the end of phase two, there was a significant (p < 0.05) increase in 15N content in egg yolk from hens fed the 50 and 250 ppm CCC diets and in albumin from hens fed the 250 ppm CCC diet. The estimated 15N-CCC residue was 1.71, 6.64, 28.80 ppm in egg yolk and 1.58, 1.08 and 4.50 ppm in albumin from hens fed 5, 50 and 250 ppm CCC, respectively. The CCC residue, from quantitative analysis ranged from 0.21 to 0.93 and 0.93 to 2.43 ppm in yolk of hens fed 50 and 250 ppm CCC, respectively, whereas a range of 0.40-1.46 ppm, was found in the albumin of hens fed 250 ppm. The difference in measured CCC in yolk and albumin and that estimated from 15N-CCC could have been due to breakdown products of 15N-CCC. Seven days after withdrawal of 15N-CCC, the estimated 15N-CCC residue in egg yolk decreased to 0.43, 2.45 and 15.59 ppm, on 5, 50 and 250 ppm CCC dietary treatments, respectively, and to 2.46 ppm in albumin from hens fed 250 ppm CCC. The higher increase in 15N content could have been due to a higher incorporation of 15N-CCC into yolk than albumin during the process of rapid yolk deposition. This experiment showed that consumed CCC is distributed both into yolk and albumin in a dose dependent manner and that CCC is metabolized in laying hens. However, the level of CCC in the diet which could lead to accumulation of detectable CCC levels in eggs as observed in this study, is much higher than the established maximum residual limits in grains.     

硒对镉在鸡体内分布的影响

本试验按照在日粮中分别添加45ppm Cd、45ppm Cd 5ppm Se、45ppm Cd 10ppmSe、45ppm Cd 15ppm Se和仅饲喂基础日粮的处理方法,将成年蛋鸡100只分成5组,对各组鸡在试验40、60、90、120d不同时期肝、肾、心、肌肉组织硒、镉的含量进行了检测.结果表明,硒可降低镉在组织器官的蓄积,且在本试验条件下,随着日被硒水平的增加,其降低效果超明显;硒对镉损害的保护效应,主要取决于日粮中适宜的Sc/Cd摩尔比值,其最适Se/Cd摩尔比约为1:3.     

Residues of sulphadimidine and its metabolites in eggs following oral sulphadimidine medication of hens

The depletion of sulphadimidine (SDM) and its N4-acetyl and hydroxy metabolites was studied in eggs laid by hens after administration of either a single or multiple oral dosages of 100 mg SDM/kg. During medication and until 1 day after the last dose, the SDM and its metabolite concentrations in the egg white exceeded those in the egg yolk and reflected the plasma levels. In the period starting 2 days after the (last) dosage, the SDM concentration in the yolk became higher than in the egg white, and the drug depletion curves ran parallel. The mean maximum amount of SDM found in the whole egg was 1500 micrograms after a single and 1280 micrograms after multiple dosage. In eggs, traces of the N4-acetyl and 6-methylhydroxy metabolites could be detected (mainly in the egg white), and their concentrations were approximately 40 times lower than those of the parent drug. A highly significant correlation (P less than 0.005) was found between the development stage of the oocyte at the time of (last) medication and the amount of SDM found in the egg that developed from it. A period of 7 or 8 days after the (last) dosage of 100 mg SDM/kg/day is required to obtain SDM levels below 0.1 micrograms/g egg.     

The distribution of lipoprotein lipase in tissues of the domestic fowl and the effects of feeding and starving

Lipoprotein lipase (E.C. 3.1.1.3) has been detected and assayed in heart muscle and adipose tissue of immature male, immature female and egg laying female domestic fowl. The levels of the enzyme in heart muscle were similar in the three classes of birds studied, but the level of the enzyme in the adipose tissue of immature birds was much higher than in that of laying hens. On starving for 22 h or 72 h the level of the enzyme increased in both heart muscle and adipose tissue of immature males. The enzyme could not be detected in liver tissue or ovary tissue from laying hens. Tissue levels of lipoprotein lipase are not a sensitive index of the state of lipid metabolism in the domestic fowl.