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.

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.

Efficacy of peritoneal dialysis of tolbutamide in rats under conditions of the plasma unbound fraction being increased.

Peritoneal dialysis of a highly protein-bound compound, tolbutamide, was examined in rats to clarify whether the efficacy of the peritoneal dialysis of such compounds increases proportionally as their unbound fractions increase. As expected, it was shown that the tolbutamide concentration of the peritoneal dialysate rose as the unbound fraction of tolbutamide increased. However, the efficacy of peritoneal dialysis of tolbutamide was proportionally elevated only when the unbound fraction was slightly increased by sulfamethoxazole treatment. When the unbound fraction of tolbutamide was increased 7.8 times by sulfadimethoxine treatment, the dialysis efficacy was increased to only 58% of that expected. This discrepancy between the observed and expected values regarding dialysis efficacy was more marked when experiments were performed in rats with experimentally induced acute renal failure. Pharmacokinetic analysis indicated that the intrinsic dialysis clearance of tolbutamide decreased when its unbound fraction was greatly increased. These findings suggest that peritoneal dialysis may be mediated not only by passive diffusion, but also by concentration-dependent processes. The efficacy of the peritoneal dialysis of therapeutic compounds may be overestimated if the estimation is based only on their unbound fraction measured under control conditions.

Use of sulfadimethoxine in intensive calf farming: evaluation of transfer to stable manure and soil.

After prophylactic treatment of 50 calves with 62mgkg(-1)day(-1) of sulfadimethoxine (SDM) for five days, the levels of the drug over time were followed in feces, bedding and stable manure, and then in the soil of a manured field and surrounding drainage courses. Analysis were done by HPLC after applying to the different matrices a quick and simple extraction procedure. The half-life of the drug in bedding was very short (24h). In stable manure the degradation rate of the drug slowed down and the calculated half-life was 64 days, with 390microgkg(-1) of SDM still detectable after three months maturation. However, in a five months matured stable manure obtained from other groups of calves subjected to the same prophylactic treatment, levels of SDM were <50muicrokg(-1) (LOD of the analytical method). After field fertilization with this manure, no traces of SDM were found in soil (LOD 10microgkg(-1)) or in the water (LOD 2microgl(-1)) from the surrounding drainage courses. Using the internationally recognised DAPHTOXKIT-Ftrade mark, a SDM toxicity test toward Daphnia magna was performed in the range 10-100mgl(-1). The test gave negative results both after 24 and 48h, confirming that microcrustaceans are less sensitive than other models to the toxicity of antibacterials. However, based on data from other authors, concerning algal toxicity and microbial inhibition, and on the analytical results from the current field study, the calculated worst-case EC50/PEC ratio for SDM both in freshwater and in soil was still >1000.

Renal selective N-acetyl-L-gamma-glutamyl prodrugs: studies on the selectivity of some model prodrugs.

1. In this study, a number of structurally different N-acetyl-L-gamma-glutamyl prodrugs were investigated with respect to selective uptake by the kidney in male Wistar rats. 2. All prodrugs were tested in vitro in rat kidney slices and kidney homogenate to study their uptake and conversion. It was found that the prodrugs of para-nitroaniline (agPNA), aminophenyl acetic acid (agAFA), sulphamethoxazole (agSM), sulphadimethoxine (agSDM), propranolol (agPP) and metoprolol (agMP) were accumulated by a probenecid-sensitive carrier. The prodrug of 4'-aminoantipyrine (agAAP) was not accumulated by a probenecid- or buthionine sulphoximine-sensitive carrier. Unlike all other prodrugs, agAAP and agMP were not, or only a very limited extent converted to the parent compound in vitro. 3. agPNA, agAFA and agPP were also investigated in vivo. The tissue distribution of the prodrugs and the parent drugs was established, as was their urinary excretion and pharmacokinetic behaviour. agPNA and agAFA showed selective uptake by the kidney, in contrast to agPP which accumulated in the liver. The distribution of the parent compounds following prodrug administration was as follows: agPNA was found in kidney and plasma: agAFA in kidney only; agPP in liver only. 4. The factors which determine the selectivity of N-acetyl-L-gamma-glutamyl prodrugs are discussed. The main factors are: the transport into the kidney, the conversion rate, the residence time of the prodrug in the kidney and the presence or absence of competition for uptake and conversation by other tissues, e.g. the liver. It is concluded that this prodrug approach offers the possibility of delivering drugs selectively to the kidney, but also that it is not universally applicable.

Disposition of sulfadimethoxine in cattle: inclusion of protein binding factors in a pharmacokinetic model.

Sulfadimethoxine was administered intravenously and orally to four cattle, and plasma and urine samples were collected at various times postdose. Modeling these data with a linear pharmacokinetic model gave unsatisfactory fits, and the data were subsequently fitted to a one-compartment model with saturable protein binding. The saturable protein binding model included the usual linear excretion and elimination processes as well as protein binding parameters. The values obtained in vivo for the binding constant, 5.01 x 10(4) M-1, and the total protein concentration, 7.89 x 10(-4) M, compared favorably with previously reported in vitro values. These results indicate that protein binding can be successfully included in a pharmacokinetic model.

In situ perfusion system for oral mucosal absorption in dogs.

To evaluate oral mucosal absorption of drugs in dogs, a newly designed in situ perfusion system with a circulating perfusion chamber was developed. The utility of the perfusion system was investigated by using three drugs: salicylic acid (SA), sulfadimethoxine (SM), and diltiazem (DIL). The oral mucosal absorption of the drugs could be adequately described by first-order rate processes. The absorption rate was independent of the amount of un-ionized drug, which varied with the pH of the solution. The absorption of SA was similar for various oral mucosal sites and for repeated experiments using the same site. Pharmacokinetic analysis for the plasma or medium concentration of SA after perfusion showed that SA was absorbed at the rate constant of 0.071 h-1, and that approximately 70% of SA absorbed from oral mucosa was transferred to the circulating blood.

Sulphadimethoxine and Azolla filiculoides Lam.: a model for drug remediation.

Plants can be an interesting tool for in situ remediation of drug contaminated waters. In a laboratory model Azolla filiculoides Lam., an aquatic fern known to absorb pollutants, has been exposed to an environmental persistent antibiotic commonly used in intensive farming, sulphadimethoxine (S), to test its bioremediation capability. In a 5 week experiment, plants were cultivated outdoor at four drug concentrations (50, 150, 300 and 450 mg l(-1)) in N-free mineral medium. Drug affects growth rate (as biomass yield per week), N2-fixation, heterocyst frequency, but plants are able to survive. Notwithstanding, at all concentrations tested drug was actively removed from the medium and the accumulation in the biomass is in order of magnitude up to mg g(-1) plant dry weight (1000 ppm). Drug uptake and degradation rates increase with S concentrations in the culture medium. The efficacy of the model was very high. These results demonstrated that Azolla can be taken into consideration as a tool for sulphonamides environmental monitoring and decontamination.

Determination of sulfadimethoxine, sulfamethoxazole, trimethoprim and their main metabolites in porcine plasma by column switching HPLC.

A HPLC method for the determination of sulfadimethoxine, sulfamethoxazole, trimethoprim and their main metabolites in porcine plasma is reported. The metabolites under investigation were the N4-acetyl sulfonamides and 3'- and 4'-demethyl trimethoprim. In order to obtain a sensitivity of 25-50 ng ml-1, the application of column switching HPLC was investigated. An on-line preconcentration of the drugs and metabolites was preceded by an off-line sample pre-treatment. Parent compounds and metabolites were separated by reversed-phase HPLC followed by UV-detection. The mean recoveries for 4'-demethyl trimethoprim were greater than 80% while the mean recoveries for the other compounds were greater than 90%. Application of the method for analysis of plasma samples obtained from pharmacokinetic studies is described.

Differential effects of ketoprofen on the pharmacokinetics of sulphadimethoxine in fast and slow acetylator rabbits.

Intravenously co-administered ketoprofen decreased the plasma concentration of sulpha-dimethoxine (SDM) after intravenous bolus administration to fast acetylator rabbits, and significantly increased the total body clearance (CLtot) and steady-state volume of distribution (Vdss) of SDM. On the other hand, ketoprofen had little effect on the plasma concentration of SDM in slow acetylator rabbits. When SDM was intravenously administered in combination with ketoprofen, an increase in the plasma concentration of N4-acetylsulphadimethoxine, a major metabolite of SDM that strongly displaces SDM from its binding sites, was observed in all rabbits, but the increase was much larger in fast acetylators. We conclude that the acetylation capacity for SDM is a factor determining the pharmacokinetic interaction between SDM and ketoprofen in rabbits.

Renal tubular excretion of the N4-acetyl metabolites of sulphasomidine and sulphadimethoxine in the dog.

To investigate whether dogs are able to excrete acetylated drugs by active transport, the plasma kinetics and renal excretion of the N4-acetyl metabolites of sulphasomidine and sulphadimethoxine were studied in the beagle dog after a rapid intravenous bolus injection. Two doses of N4-acetylsulphasomidine (1050 and 105 mg) and one dose of N4-acetylsulphadimethoxine (472 mg) were administered on separate occasions. The renal clearance (CLR) was as follows: N4-acetylsulphasomidine (1050 mg) 34 mL min-1; N4-acetylsulphasomidine (105 mg) 28 mL min-1; and N4-acetylsulphadimethoxine (472 mg) 24 mL min-1. CLR was higher than expected on the basis of the measured glomerular filtration rate, indicating that the N4-acetyl metabolites may be excreted by the renal tubules by active tubular transport. Saturation of the excretion process of N4-acetylsulphasomidine occurred with a transport maximum of 930 +/- 190 micrograms min-1 and a Michaelis-Menten constant of 37 +/- 10 micrograms mL-1. It may be concluded that the dog renal organic anion transport system is able to secrete acetylated sulphonamides.

Distribution and elimination of sulphadimethoxine and its metabolites in treated chicken.

Sulphadimethoxine (SDM), and its metabolites, N4-acetyl SDM, N1-(2-methyl-6-hydroxy-4-pyrimidinyl) sulphanilamide (6-OH-SDM), N1-(6-methyl-2-hydroxy-4-pyrimidinyl) sulphanilamide (2-OH-SDM), N1-(2,6-dihydroxy-4-pyrimidinyl) sulphanilamide (2,6-diOH-SDM) and SDM N1-glucuronide in chicken tissues were extracted, partially purified by Bond Elute SCX cartridges, and assayed and identified by HPLC/LC-MS after administration of SDM to chickens. During the administration and 24 h after withdrawal, SDM and 6-OH-SDM were observed in almost all tissues and excreta. N4-Acetyl SDM and 2,6-diOH-SDM were observed in some tissues, but 2-OH-SDM and SDM N1-glucuronide were observed in a few limited tissues. Twenty four hours after withdrawal, SDM and its metabolites, except 6-OH-SDM, decreased. SDM and its metabolites were eliminated from all tissues within 48 h of withdrawal.

Influence of gestation on the pharmacokinetics of four sulphonamides in goats.

The influence of gestation on the pharmacokinetics of four sulphonamides was studied in goats before, during and after pregnancy. Similar doses were given as intravenous boluses of 50 mg kg-1 each. Results were compared with those of non-pregnant goats to eliminate seasonal effects. With sulphadimidine elimination was mainly apparently first-order. In gestating goats the mean residence times decreased and mean plasma clearance rates increased with sulphadimidine during pregnancy, but this effect was continued after kidding at least until the end of May. The same happened with sulphadimethoxine, but sulphisomidine was not affected. In contrast to the other sulphonamides the mean residence time of sulphadoxine showed a maximum in February in gestating goats, while mean plasma clearance remained constant during and after pregnancy, at a lower level than in September. The mean plasma clearance of sulphadoxine decreased significantly from September to February in the non-pregnant control goats. In May five of six control goats and two of six goats which had kidded showed capacity-limited elimination against only two control goats in the foregoing experiments. With sulphadoxine one animal in the gestation group, but not the same one in each experiment, showed capacity-limited elimination against one, four and three in the control group in December, February and May, respectively. Distribution volumes increased significantly during and after pregnancy with sulphisomidine and sulphadimethoxine. A decrease in distribution volumes was seen in control goats with sulphadimidine, sulphisomidine and sulphadoxine, but was only significant for sulphadoxine. The pregnant uterus could not be recognised as an extra compartment, either in distribution volume nor in the pharmacokinetic model.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and body fluid and endometrial concentrations of ormetoprim-sulfadimethoxine in mares.

Six healthy adult mares were each given an oral loading dose of ormetoprim(OMP)-sulfadimethoxine (SDM) at a dosage of 9.2 mg of OMP/kg and 45.8 mg of SDM/kg, followed by four maintenance doses of 4.6 mg of OMP/kg and 22.9 mg of SDM/kg, at 24 h intervals. Ormetoprim and SDM concentrations were measured in serum, synovial fluid, peritoneal fluid, cerebrospinal fluid, urine and endometrium. The highest mean serum OMP concentration was 0.92 micrograms/mL 0.5 h after the first dose; the highest mean SDM concentration was 80.9 micrograms/mL 8 h after the first dose. The highest mean synovial fluid concentrations were 0.14 microgram of OMP/mL and 28.5 micrograms of SDM/mL 12 h after the first dose. The highest mean peritoneal fluid concentrations were 0.19 micrograms of OMP/mL 6 h after the first dose and 25.5 micrograms of SDM/mL 8 h after the fifth dose. The highest mean endometrial concentrations were 0.56 micrograms of OMP/g and 28.5 micrograms of SDM/g 4 h after the fifth dose. The mean cerebrospinal fluid concentrations were 0.08 micrograms of OMP/mL and 2.1 micrograms of SDM/mL 5 h after the fifth dose. Mean trough urine drug concentrations were greater than or equal to 0.4 micrograms of OMP/mL and greater than or equal to 172 micrograms of SDM/mL. Two of the mares were each given a single intravenous (IV) injection of OMP and SDM at a dosage of 9.2 mg of OMP/kg and 45.8 mg of SDM/kg. Excitation and muscle fasciculations were observed in both mares after IV administration and all scheduled blood samples could be collected from only one of the two mares.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of sulfadimethoxine withdrawal time from milk. Part II: Statistical assessment.

A statistical method is proposed to establish milk discard time for the data set described in Part I (preceding paper). Results are compared with those from the Food and Drug Administration (FDA)-recommended method. The milk discard time is established on the basis of a calculated tolerance limit. This limit provides 95% confidence that 99% of the population residue would assay below the permitted concentration (10 ppb for SDM). Unlike the FDA method, the proposed method allows easy calculation and requires no assumptions in drug depletion rate over time. For a permitted concentration of 10 ppb, both methods confirm the present 60-h discard time for SDM when it is assumed that no more than 1/3 of the milk came from treated cows.

Determination of sulfadimethoxine withdrawal time from milk. Part I: Dosing, sampling, and assay.

This study was undertaken to determine whether present regulations for discarding milk from cows treated with sulfadimethoxine (SDM) can be supported by modern analytical methodology. Two groups of milking cows (10 in first group; 11 in the second) were treated orally with SDM at the recommended dose levels for 5 days. The SDM concentration in the milk was determined with 4 methods (Charm Inhibition Assay [CIA], Charm II, enzyme linked immunosorbent assay, and liquid chromatography) during the treatment and the subsequent withdrawal periods. The results of the 4 assays were compared.

Tissue residues of sulfadimethoxine following dietary administration to broiler-chickens.

Broilers were divided into four groups and the first group served as the control. The second, third and fourth groups were given feed containing 25, 50 and 100 mg/kg of sulfadimethoxine (SDM), respectively, for 21 days, and thereafter each group received the SDM free feed. On certain days during the experiment period, three broilers in each group were sacrificed and tissues, including blood, heart, liver, spleen, gizzard, thigh muscle, breast muscle and fat, were collected and residual SDM were determined by HPLC. Two days after withdrawal, SDM in each tissue had decreased to below the detection limit of 0.01 microgram/g.

Pharmacokinetics of sulfadimethoxine in skin of broiler-chicken after single and multiple intravenous injections.

Pharmacokinetics of sulfadimethoxine (SDMX) in skin of broiler chicken after intravenous and in-drinking-water administrations were investigated to examine the reason for a longer residue of SDMX in the skin which was observed in the residue study after administration via drinking water at a concentration of 1,000 ppm. The decay curve of SDMX in the skin after single intravenous injection of 200 mg/kg, the highest dose, was fitted to the two compartment model with T1/2 of 4.4 hrs in the first elimination phase and 173 hrs in the second one. The extrapolated concentrations in the skin at 24 hrs after the injection were calculated to be 69.0 micrograms/g for the 1st phase and 0.11 micrograms/g for the 2nd phase. The decay curves in the skin after single injection of 30 and 100 mg/kg were fitted to the one compartment model with T1/2 of 3.2 and 5.7 hrs, respectively. Dividing a high dose into 3 to 5 doses and injecting sequentially with intervals of the previously measured T1/2, SDMX concentrations in the skin were about half of those in the plasma and ran parallel. The plasma concentration-time curves after single intravenous injection of SDMX more than 100 mg/kg showed nonlinear kinetics with concentrations over 100 micrograms/ml for 12-30 hrs after the injection. By administration of SDMX via drinking water, a sustained residue curve of SDMX in the skin at 1,000 ppm reported previously was not observed at 500 ppm.(ABSTRACT TRUNCATED AT 250 WORDS)

Sulfadimethoxine residue in broiler-chicken skin.

The disposition and elimination of sulfadimethoxine (SDMX) in the skin of broiler-chickens were investigated. The administration of SDMX, in drinking water, at a concentration of 1,000 ppm for 5 days demonstrated that the SDMX was eliminated much more slowly from the skin than from the other tissues or plasma. These results were duplicated and confirmed in another experiment, in which a single dose of 200 mg/kg BW of SDMX was administered via a stomach tube. No significant difference in the SDMX residue level was observed between the broiler-chickens that had their skin surface sealed versus the non-sealed animals and that had ingested SDMX in their drinking water. This illustrated the higher SDMX residue in the skin was not attributable to external SDMX contamination from the drinking water, feces or urine. In addition, there was no significant difference among the SDMX residue concentrations in the thoracic, dorsal and leg skin samples, following an intravenous injection of SDMX (30 mg/kg BW). This indicated that the SDMX was distributed evenly throughout the entire skin area of the broiler-chickens.

Tissue sulfonamide concentration and correlation in turkeys.

Nineteen hen turkeys (10 to 12 kg each) were used in a feeding study to determine sulfadimethoxine and sulfaquinoxaline concentrations in blood serum, liver, and skeletal muscle, as well as the respective ratios at selected withdrawal intervals. Two feeds were prepared by use of premixes to achieve 60 mg of sulfadimethoxine/kg and 100 mg of sulfaquinoxaline/kg, respectively. Each of the medicated feeds was given to 9 turkeys for 7 days. The turkeys were then fed nonmedicated feed at intervals from 24 to 56 hours and were slaughtered. One turkey was used as control. The serum/liver and serum/muscle ratios for sulfaquinoxaline were 60 to 70% higher than for sulfadimethoxine. However, the liver/muscle ratio for both sulfonamides was equivalent, approximately 3. Disposition of both sulfonamides approximated first-order pharmacokinetics. The calculated half-life of sulfadimethoxine was half that of sulfaquinoxaline, approximately 16 vs 30 hours. The coefficients of variation in the serum/tissue ratios for both sulfonamides were between 13% and 25% for serum/liver and less than 15% for serum/muscle, indicating excellent potential for using serum as a predictor of actionable concentrations of sulfonamide residues.