Effect of dissolution rate of sulfamethazine from tablets on absorption and excretion of sulfamethazine.
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Drug Compounding↗
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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.
Animal Feed↗
A method for the quantification of low concentration sulfamethazine residues in milk based on molecularly imprinted clean-up and surface preconcentration at a Nafion-modified glassy carbon electrode.
An electrochemical method for the determination of sulfamethazine at a low concentration level (25 microgl(-1)) in milk is reported. The method involves sample clean-up and selective preconcentration of sulfamethazine with a molecularly imprinted polymer (MIP), and a further electrode surface preconcentration of the analyte at a Nafion-coated glassy carbon electrode (GCE). Square wave (SW) oxidative voltammetry of accumulated sulfamethazine was employed for its quantification. Sulfamethazine electrode preconcentration was carried out in 0.1 moll(-1) Britton-Robinson buffer of pH 1.5, and by applying 5 min of accumulation at open circuit. A linear calibration graph was obtained for sulfamethazine at the Nafion-modified GCE over the 1.0x10(-8) to 1.0x10(-6)moll(-1) concentration range, with a detection limit of 6.8x10(-9)moll(-1) (1.9 microgl(-1)). This detection limit is remarkably better than those reported previously in the literature using electroanalytical techniques. Although the detection limit achieved was sufficient to allow the direct determination of sulfamethazine at the concentration level required in milk, a sample clean-up was shown to be necessary to obtain analytically useful SW voltammograms. This was accomplished by processing the deproteinized milk through a cartridge containing a molecularly imprinted polymer for sulfamethazine, also allowing a selective preconcentration of the analyte. Elution of the analyte from the MIP cartridges was carried out with 2 ml of a (9:1) MeOH:acetic acid mixture. Determination of sulfamethazine in milk samples was accomplished by interpolation into a calibration graph constructed with sulfamethazine standard solutions which were subjected to the same procedure than the deproteinized milk samples. Results obtained for five samples, spiked at the 25 microgl(-1) level, showed a mean recovery of (100+/-3)%.
Animals↗
Extraction and detection of sulfamethazine in spray-dried milk.
Processes that reduce moisture content of fluid milk may result in a high concentration of animal drug residues that are undetectable in the fluid milk on the basis of the same weights. The objectives were to determine the amount of sulfamethazine in spray-dried milk powder manufactured from fluid milk contaminated with sulfamethazine and to determine the effectiveness of supercritical fluid extraction as a means to extract sulfamethazine from dry milk powder. Fluid whole (3.25% fat) and skim milks with sulfamethazine added at concentrations of 5, 10, and 100 ppb were spray-dried. Based on total solids, observed concentrations were 493 and 523 ppb in skim and whole dry milk powders, respectively, compared with fluid milk containing 100 ppb of sulfamethazine as determined by HPLC. The increase in sulfamethazine concentration from fluid to dry milk was also measured quantitatively by a microbial receptor assay and an ELISA. Poor recoveries and variability in data were possibly due to binding of sulfamethazine to undetermined milk components. Dry milk powder with measured concentrations of sulfamethazine was treated with supercritical CO2. Sulfamethazine was not detectable in the extracted dry milk powder by microbial receptor assay or ELISA.
Animals↗
Depletion kinetics of 14C-sulfamethazine [4-amino-N-(4, 6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide] metabolism in swine.
Swine weighing 60-70 kg were orally administered 14C-sulfamethazine [4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide] at 12-hr intervals for 7 days (165 mg/dose; 0.126-5.04 mCi/mmol). The animals were sacrificed at 8 hr or 2, 5, or 10 days after the last dose was given and tissues were assayed for total 14C activity. The presence of 14C-labeled sulfamethazine, N4-acetylsulfamethazine, desaminosulfamethazine, and the N4-glucose conjugate of sulfamethazine in blood, liver, kidney, skeletal muscle, and adipose tissue was verified by HPLC and GC-MS analysis. Total 14C residue levels in all tissues examined had dropped to less than 0.1 ppm sulfamethazine equivalents by day 10 of the depletion period. The mean half-life (t1/2) for sulfamethazine, the N4-glucose conjugate of sulfamethazine, and N4-acetylsulfamethazine was estimated to be 0.8 day. In some tissues, the depletion of the N4-glucose conjugate of sulfamethazine and N4-acetylsulfamethazine had decreased significantly between days 5 and 10, resulting in an approximate doubling of the t1/2 for that period. In contrast, the half-life of desaminosulfamethazine varied from a mean of 0.96 day during the 8-hr-5-day depletion period to 3.7-9.1 days during the 5- 10-day depletion period. In most tissues, the t1/2 for the 14C-activity in the methanol-insoluble fraction increased by 3-5-fold between days 5 and 10 of the depletion period. No predictable relationship was observed between blood sulfamethazine or metabolite levels and total residue levels in the tissues.
Adipose Tissue↗
Relationship of sulfamethazine in swine diets and resultant tissue concentrations, using Tishler and gas liquid chromatographic methods.
Sulfamethazine (110 mg/kg of feed) was fed to 4 groups of pigs for 10 days. Each group was then fed withdrawal rations containing 0, 1.1, 11.0, or 110.0 mg/kg of feed for 10 days before slaughter. A 5th group was fed a sulfamethazine-free diet only. Fat, kidney, liver, and muscle from each pig were analyzed by several laboratories, using the Tishler Bratton-Marshall (BM) and gas liquid chromatographic (GLC) methods. Mean background (BG) amounts of sulfamethazine, as measured in control tissues, were essentially negligible using GLC; however, BM BG values (mean +/- SD), expressed as milligrams of sulfamethazine per kilogram of edible animal tissue (ppm) were: fat 0.019 +/- 0.003, kidney 0.048 +/- 0.012, liver 0.053 +/- 0.034, and muscle 0.018 +/- 0.017. Regression of tissue sulfamethazine on feed sulfamethazine, as measured by GLC and BM adjusted for BM-BG values, yielded essentially linear plots. Values obtained by GLC and corrected BM were highly correlated, but the variability was higher, using GLC. The linear model predicted that the dietary sulfamethazine required to produce 0.1 ppm in liver as measured by the BM, BM-BG, and GLC were 1.6, 2.8, and 3.4 ppm, respectively. The concentrations necessary to produce 0.1 ppm in muscle were 5.3, 6.2, and 5.5 ppm. The thin-layer chromatographic method of screening swine plasma was a good predictor of tissue sulfamethazine values.
Animal Feed↗
Pharmacokinetic model for predicting sulfamethazine disposition in pigs.
Concentration of sulfamethazine was measured in plasma and tissues (fat, liver, kidney, spleen, lungs, and skeletal muscle) of pigs given the drug IV and PO. The plasma concentration vs time curve was best described by a 2-compartment model, with a distribution half-life of 0.46 hour and an elimination half-life of 16.9 hours. Bioavailability after oral administration was 85.8 +/- 5.3%. The tissue and plasma sulfamethazine concentration vs time data were used to develop a multi-compartment pharmacokinetic model of sulfamethazine disposition in pigs. Plasma and tissue concentrations of sulfamethazine in pigs were measured at various intervals after multiple oral doses of sulfamethazine, and were compared to concentrations predicted by the model. Model predictions for tissue concentrations of sulfamethazine after addition of the drug to feed (110 micrograms/g of feed for 98 days; 550 micrograms/g for 30 days) were compared to results from other studies. The model accurately predicted the number of days for sulfamethazine concentration to fall below 0.1 micrograms of tissue/g (0.1 ppm, the tolerated concentration) in various tissues.
Administration, Oral↗
Disposition of sulfonamides in food-producing animals: concentrations of sulfamethazine and its metabolites in plasma, urine, and tissues of lambs following intravenous administration.
A sensitive, precise, and efficient analytical method for sulfamethazine in the liver, kidney, heart, skeletal muscle, and fat of lambs is reported. The method involves freezing cubed tissue in liquid nitrogen, powdering the frozen tissue in a liquid nitrogen-cooled blender, and extracting the tissue on a sodium sulfate column with chloroform:acetone. A thin-layer chromatographic procedure capable of separating and quantitating sulfamethazine and 3 metabolites (acetyl, hydroxylated, and polar conjugate(s) in lamb urine is also reported. Sulfamethazine was administered intravenously (107.25 mg/kg body weight) to 14 cross-bred ewe lambs. The concentration of sulfamethazine in plasma and tissues and sulfamethazine and its metabolites in urine were determined in samples collected at specific postdosing times. The concentration of sulfamethazine in plasma exceeded 5 mg/100 ml for 18 to 24 hours after drug administration. The excretion of diazotizable materials in the urine was essentially complete at the 60th hour after dosing. The drug was excreted in the urine as sulfamethazine, a hydroxylated metabolite, acetylsulfamethazine, and polar conjugate(s). Tissue concentrations of the drug were greatest in the kidney and less (in decreasing quantities) in liver, heart, skeletal muscle, body fat, and omental fat.
Animals↗
Influence of chronic obstructive lung disease on the disposition of an acidic drug (sulfamethazine).
The influence of chronic respiratory failure (CRF) on the pharmacokinetics of an acidic drug has been studied in 11 patients and in eight normal volunteers who received 10 mg/kg of oral sulfamethazine. Blood and urine samples were collected for 24 and 48 hours, respectively. No differences were observed in the rate of sulfamethazine absorption, but bioavailability was decreased when compared with control subjects. Sulfamethazine volume of distribution (Vd) was larger in patients than in control subjects. These differences in Vd may be secondary to an increase in sulfamethazine unbound fraction. No differences were observed in sulfamethazine elimination. It is concluded that in patients with CRF sulfamethazine bioavailability decreases, and Vd increases secondary to a decrease in binding. Despite the fact that plasma concentrations of the test drug will be decreased, the administration of higher doses may not be advisable.
Absorption↗
Effect of sulfamethazine on phenobarbital and benzo[a]pyrene induced hepatic microsomal mixed function oxidase system in rats.
Administration of sulfamethazine (300 mg/kg, i.p., single dose) to phenobarbital (80 mg/kg, i.p., 3 days) pretreated rats showed significant decrease in microsomal protein, electron transport components and drug metabolizing enzyme activities, compared with phenobarbital administration alone. Induction of mixed function oxidase enzymes due to phenobarbital was not affected by the pretreatment of sulfamethazine. Sulfamethazine administration to benzo[a]pyrene (20 mg/kg, i.p., 2 days in oil) pretreated rats showed no significant change, but there was a slight decrease in cytochrome P450 and aminopyrine N-demethylase activity, compared with benzo[a]pyrene administration alone. A significant inhibition was observed in aminopyrine N-demethylase activity due to in vitro addition of sulfamethazine (3.5 mM) to microsomal incubations from untreated, sulfamethazine, phenobarbital and benzo[a]pyrene-treated rats. The results indicate that the phenobarbital induced cytochrome P450 is more susceptible to sulfamethazine than benzo[a]pyrene induced cytochrome P450.
Animals↗
Effects of the antimicrobial agent sulfamethazine on metolachlor persistence and sorption in soil.
Recent monitoring investigations have shown that antimicrobial agents used in veterinary medicine can cause non-point source contamination of soils through manure spreading. In the present study, the effect of the antimicrobial agent sulfamethazine (sulfadimidine) on degradation and sorption of the herbicide metolachlor in a sandy loam soil was studied. In soil samples treated with sulfamethazine at two concentrations (15 and 150 microg kg(-1) soil), metolachlor persistence was not different than of that observed in untreated samples. These results were supported by the absence of effects of both sulfamethazine concentration levels on the size of the culturable soil bacteria population. Equilibrating soil samples with metolachlor solutions containing equivalent sulfamethazine concentrations did not lead to any significant effects on metolachlor sorption, suggesting that, under the conditions of the present experiment, sulfamethazine did not affect metolachlor bioavailability in soil. This laboratory investigation showed that concentrations of sulfamethazine in the microg kg(-1) range did not cause significant effects on metolachlor degradation and sorption thus not affecting the main processes ruling its environmental fate in soil.
Acetamides↗
Confirmatory method for sulfamethazine residues in cattle and swine tissues, using gas chromatography--chemical ionization mass spectrometry.
A gas chromatographic (GC) method has been reported for the determination of sulfamethazine residues in cattle and swine tissues. The extracts from this procedure were found to be directly amenable to examination by gas chromatography-mass spectrometry (GC-MS), allowing positive confirmation of an apparent residue of sulfamethazine. Chemical ionization mass spectrometry (CIMS) was chosen as the MS technique because it generated an ion indicative of intact sulfamethazine and fragment ions indicative of the amine functionality and sulfanil moiety. Positive ion (PI) chemical ionization mass spectrometry was adequate by itself for a confirmatory technique. Negative ion (NI) chemical ionization mass spectrometry alone could not be used for the confirmatory analysis of sulfamethazine, but it did offer a means to check the quantitative data from the positive ion analyses and provided complementary confirmatory data. Satisfactory recoveries were obtained for sulfamethazine in swine and cattle tissues at the tolerance level of 0.1 ppm. Apparent sulfamethazine residues in control tissues were less than 0.01 ppm.
Animals↗
Effects of nocloprost (9 beta-chloro-16,16-dimethyl PG E2) on absorption and disposition of antipyrine and sulfamethazine in healthy volunteers.
Prostaglandins are known to interfere with drug metabolizing processes. Nocloprost (9 beta-chloro-16,16-dimethyl PG E2) is a promising new cytoprotective prostaglandin in clinical evaluation for the treatment of ulcer disease and prophylaxis of gastric lesions caused by NSAID. Pharmacokinetic interactions of 400 micrograms nocloprost with 15 mg/kg antipyrine and 500 mg sulfamethazine (all given p.o.) were studied with a controlled, single-blind crossover trial in 16 healthy male volunteers (age 22-25 years, body weight 63-94 kg, body height 175-187 cm) in order to measure potential interferences with oxidative and conjugative drug metabolism. All individuals were extensive metabolizers of debrisoquine, 9 were slow and 7 rapid acetylators of sulfamethazine. Antipyrine and its major metabolites were measured in serum respectively, urine with the HPLC-method, sulfamethazine and its acetylated metabolite with a colorimetric technique. Nocloprost premedication (30 min prior to the test drugs) did neither interfere significantly with the oxidative processes involved in the disposition of antipyrine nor with the N-acetylation of sulfamethazine. Higher metabolic and renal clearance values of sulfamethazine in slow acetylators were most likely the result of the affected drug absorption. Nocloprost significantly reduced absorption rates of antipyrine and sulfamethazine in the group of slow but not of rapid acetylators. The extent of bioavailability remained unchanged. This phenomenon was certainly caused by the effects of the cytoprotective prostaglandin on those gastrointestinal functions which are determinants of drug absorption.
Acetylation↗
Disposition of sulfonamides in food-producing animals: pharmacokinetics of sulfamethazine in lambs.
Previously reported plasma and urine concentrations of unchanged sulfamethazine and 3 metabolites following intravenous administration of sodium sulfamethazine to young ewe lamb were fitted to a linear pharmacokinetic model in which sulfamethazine itself obeyed 1-compartment phamacokinetics. The average rate constant for overall elimination of sulfamethazine was 0.096 +/- 0.023 hours-1, corresponding to a biological half-life of 7.2 +/- 1.7 hours. The results of residue analysis of 8 tissues obtained at slaughter showed that tissue and plasma concentrations and urine output of unchanged sulfamethazine fell parallel throughout the experiment. The results indicate that determination of the plasma concentration or urinary output of sulfamethazine can be substituted for tissue residue analysis to determine contamination of carcasses above specified tolerance limits.
Animals↗
Gas chromatographic-mass spectrometric determination of sulfamethazine in animal tissues using a methyl/trimethylsilyl derivative.
A method is described for the determination of sulfamethazine in swine tissues by GC-MS. Samples are extracted with chloroform-acetone, followed sequentially by two solid-phase clean-up steps using silica gel and SCX ion exchange. The extracts are then partitioned between sodium dihydrogenphosphate (0.1 mol l-1) and methyl tert-butyl ether, the organic phase is evaporated to dryness and the sulfamethazine subjected to a double derivatization via methylation and silylation and determined by GC-MS in the selected-ion monitoring mode. Quantification is achieved by measuring the ratio of the abundances of the M-65 (-HSO2) ions of the derivatives of sulfamethazine and the internal standard, [phenyl-13C6]sulfamethazine, at m/z 299 and 305, respectively. The presence of sulfamethazine can be confirmed using the abundance ratios of the ions of m/z 299, 300 (-SO2) and 349 (-CH3). Recovery values from muscle, kidney and liver spiked at 0.05, 0.2 and 0.4 ppm ranged from 86 to 114% with RSDs between 2.8 and 9.0%. The limit of detection for the assay is 0.01-0.02 ppm. The methyl/trimethylsilyl derivatives exhibited better chromatography than the commonly used N1-methyl derivatives; for the same conditions, the peak was sharper and tailing was significantly reduced.
Animals↗
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 micrograms.h/mL and AUC 1484 micrograms.h/mL; Vdarea 0.434 L/kg and Vdarea 0.374 L/kg; t 1/2 beta 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.
Animals↗
Novel approach to control sulfamethazine misuse in food-producing animals by hair analysis.
The presence of sulfamethazine residues in pig and calf hair was compared with the residual levels encountered in the corresponding edible tissues (liver and muscle) as a consequence of drug administration. Sulfamethazine up to 84.7 mg kg-1 was found in calf hair samples after a pharmacological treatment, with a significant effect of hair pigmentation. High concentrations of the parent drug were detected in calf hair for 4 weeks after administration, when sulfamethazine residues were no longer detectable in the corresponding edible tissues. In a similar way, pig hair also accumulated sulfamethazine residues up to 40.5 mg kg-1, which was more than the amount detected in the corresponding muscle and liver samples at slaughter. Hair analysis seems a suitable tool to improve the efficacy of regulatory controls, and thus the safety of the food chain and to discourage the improper use of sulfamethazine in animal farming.
Animals↗
Influence of oral administration of sulfamethazine on thyroid hormone levels in Fischer 344 rats.
Fischer 344 rats (810 of each sex) were divided into treatment groups and fed diets containing 0, 10, 40, 600, 1200, or 2400 ppm sulfamethazine. Serum samples were analyzed for levels of thyroid-stimulating hormone (TSH), total thyroxine (T4), total triiodothyronine (T3), and T3 uptake after 12, 18, or 24 mo of continuous dosing. There were no statistically significant differences in T3 levels or percent T3 uptake for either sex after any of the exposure periods. The serum T4 levels were lower (p less than 0.05) for females dosed at 1200 and 2400 ppm for 18 mo and for males dosed at 600, 1200, or 2400 ppm sulfamethazine for 24 mo than for those dosed at levels of 40 ppm or less. Serum TSH levels showed a general increasing trend (but not statistically significant) among animals receiving 600 ppm or more sulfamethazine. There was a significant dose-related reduction in (T3 + T4)/TSH ratio for both sexes (p less than 0.05) after 18 and 24 mo of exposure at dose levels of 600 ppm or more. A lack of response at 12 mo may have been due to the shorter treatment time. At each sacrifice period both sexes of rats fed sulfamethazine at 1200 and 2400 ppm had significantly heavier (p less than 0.05) thyroid weights than animals fed control diet. The heavier thyroid weights in the dosed animals may have resulted from increased TSH levels. The cause of reduction in serum T4 was not clearly evident. Therefore, the thyroid hormone to pituitary feedback mechanism apparently compensated for sulfamethazine effects in most animals. This would suggest that the thyroid gland was not irreversibly affected.
Administration, Oral↗