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This study aimed to examine the bioavailability (BA) and pharmacokinetic (PK) characteristics of sulfadiazine (SDZ) in grass carp (Ctenopharyngodon idellus) after oral and intravenous administrations. Blood samples were collected at predetermined time points of 0.083, 0.17, 0.5, 1, 2, 4, 8, 16, 24, 48, 72, and 96 hr (n = 6). The samples were extracted and purified by organic reagents and determined by the ultra-performance liquid chromatography. The software named 3P97 was used to calculate relevant PK parameters. The results demonstrated that the concentration-time profile of SDZ was best described by a one-compartmental open model with first-order absorption after a single oral dose. The main PK parameters of the absorption rate constant (K α ), the absorption half-life (t 1/2 Kα ), the elimination rate constant (K e ), the elimination half-life (t 1/2Ke ), and the area under concentration-time profile (AUC 0-∞ ) were 0.3 1/h, 2.29 hr, 0.039 1/h, 17.64 hr, and 855.78 mg.h/L, respectively. Following intravenous administration, the concentration-time curve fitted to a two-compartmental open model without absorption. The primary PK parameters of the distribution rate constant (α), the elimination rate constant (β), the distribution half-life (t 1/2α ), the elimination half-life (t 1/2β ), the apparent distribution volume (V SS ), the total clearance (CL), and AUC 0-∞ were 9.62 1/hr, 0.039 1/hr, 0.072 hr, 17.71 hr, 0.33 L/kg, 0.013 L h -1  kg -1 , and 386.23 mg.h/L, respectively. Finally, the BA was calculated to be 22.16%. Overall, this study will provide some fundamental information on PK properties in the development of a new formulation SDZ in the future and is partially beneficial for the appropriate usage of SDZ in aquaculture., (© 2020 John Wiley & Sons Ltd.)

Background: Dosing recommendations for the treatment of pregnancy-acquired toxoplasmosis are empirical and widely based on experimental data. There are no pharmacological data on pregnant women with acute Toxoplasma gondii infection under treatment with pyrimethamine (PY) and sulfadiazine (SA) and our study intends to tighten this gap., Methods: In this retrospective case-control study, we included 89 pregnant women with primary Toxoplasma infection (PT) treated with PY (50 mg first dose, then 25 mg/day), SA (50 mg/kg of body weight/day), and folinic acid (10-15 mg per week). These were compared to a group of 17 women with acute ocular toxoplasmosis (OT) treated with an initial PY dose of 75 mg, thereafter 25 mg twice a day but on the same SA and folinic acid regimen. The exact interval between drug intake and blood sampling and co-medication had not been recorded. Plasma levels of PY and SA were determined 14 ± 4 days after treatment initiation using liquid chromatography-mass spectrometry and compared using the Mann-Whitney U test at a p < 0.05 level., Results: In 23 PT patients (26%), SA levels were below 20 mg/l. Fifteen of these 23 patients (17% of all patients) in parallel presented with PY levels below 700 µg/l. Both drug concentrations differed remarkably between individuals and groups (PY: PT median 810 µg/l, 95% CI for the median [745; 917] vs. OT 1230 µg/l [780; 1890], p = 0.006; SA: PT 46.2 mg/l [39.9; 54.4] vs. OT 70.4 mg/l [52.4; 89], p = 0.015) despite an identical SA dosing scheme., Conclusions: SA plasma concentrations were found in the median 34% lower in pregnant women with PT compared to OT patients and fell below a lower reference value of 50 mg/l in a substantial portion of PT patients. The interindividual variability of plasma concentrations in combination with systematically lower drug levels and possibly a lower compliance in pregnant women may thus account for a still not yet supportable transmission risk. Systematic drug-level testing in PT under PY/SA treatment deserves to be considered.

A new sensitive voltammetric sensor for determination of sulfadiazine is described. The developed sensor is based on carbon paste electrode modified with sulfadiazine imprinted polymer (MIP) as a recognition element. For comparison, a non-imprinted polymer (NIP) modified carbon paste electrode was prepared. Cyclic voltammetry (CV) and differential pulse voltammetry (DPV) methods were performed to study the binding event and electrochemical behavior of sulfadiazine at the modified carbon paste electrodes. The determination of sulfadiazine after its extraction onto the electrode surface was carried out by DPV at 0.92 V vs. Ag/AgCl owing to oxidation of sulfadiazine. Under the optimized operational conditions, the peak current obtained at the MIP modified carbon paste electrode was proportional to the sulfadiazine concentration within the range of 2.0×10(-7)-1.0×10(-4) mol L(-1) with a detection limit and sensitivity of 1.4×10(-7) mol L(-1) and 4.2×10(5) μA L mol(-1), respectively. The reproducibility of the developed sensor in terms of relative standard deviation was 2.6%. The sensor was successfully applied for determination of sulfadiazine in spiked cow milk and human serum samples with recovery values in the range of 96.7-100.9%., (© 2013.)

A novel chemiluminescence (CL) quenching method for the determination of sulfonamides is proposed. The CL reaction between Ag(III) complex [Ag(HIO₆)₂]⁵⁻ and luminol in alkaline solution was investigated. The quenching effect of sulfonamides on CL emission of [Ag(HIO₆)₂]⁵⁻-luminol system was found. Quenching degree of CL emission was proportional to sulfonamide concentration. The effects of the reaction conditions on CL emission and quenching were examined. Under optimal conditions, the detection limits (s/n = 3) were 7.2, 17 and 8.3 ng/mL for sulfadiazine, sulfameter, and sulfadimethoxine, respectively. The recoveries of the three drugs were in the range of 91.3-110% with RSDs of 1.9-2.7% for urine samples, and 106-112% with RSDs of 1.6-2.8% for serum samples. The proposed method was used for the determination of sulfadiazine at clinically relevant concentrations in real urine and serum samples with satisfactory results., (Copyright © 2011 John Wiley & Sons, Ltd.)

A pharmacokinetic and bioavailability study of sulfadiazine combined with trimethoprim (sulfadiazine/trimethoprim) was carried out in fifteen healthy young ostriches after intravenous (i.v.), intramuscular (i.m.) and oral administration at a total dose of 30 mg/kg body weight (bw) (25 and 5 mg/kg bw of sulfadiazine and trimethoprim, respectively). The study followed a single dose, three periods, cross-over randomized design. The sulfadiazine/trimethoprim combination was administered to ostriches after an overnight fasting on three treatment days, each separated by a 2-week washout period. Blood samples were collected at 0 (pretreatment), 0.08, 0.25, 0.50, 1, 2, 4, 6, 8, 12, 24 and 48 h after drug administration. Following i.v. administration, the elimination half-life (t(1/2beta)), the mean residence time (MRT), volume of distribution at steady-state (V(d(ss))), volume of distribution based on terminal phase (V(d(z))), and the total body clearance (Cl(B)) were (13.23 +/- 2.24 and 1.95 +/- 0.19 h), (10.06 +/- 0.33 and 2.17 +/- 0.20 h), (0.60 +/- 0.08, and 2.35 +/- 0.14 L/kg), (0.79 +/- 0.12 and 2.49 +/- 0.14 L/kg) and (0.69 +/- 0.03 and 16.12 +/- 1.38 mL/min/kg), for sulfadiazine and trimethoprim, respectively. No significant difference in C(max) (35.47 +/- 2.52 and 37.50 +/- 3.39 microg/mL), t(max) (2.47 +/- 0.31 and 2.47 +/- 0.36 h), t((1/2)beta) (11.79 +/- 0.79 and 10.96 +/- 0.56 h), V(d(z))/F (0.77 +/- 0.06 and 0.89 +/- 0.07 L/kg), Cl(B)/F (0.76 +/- 0.04 and 0.89 +/- 0.07) and MRT (12.39 +/- 0.40 and 12.08 +/- 0.36 h) were found in sulfadiazine after i.m. and oral dosing, respectively. There were also no differences in C(max) (0.71 +/- 0.06 and 0.78 +/- 0.10 microg/mL), t(max) (2.07 +/- 0.28 and 3.27 +/- 0.28 h), t((1/2)beta) (3.30 +/- 0.25 and 3.83 +/- 0.33 h), V(d(z))/F (6.2 +/- 0.56 and 6.27 +/- 0.77 L/kg), Cl(B)/F (21.9 +/- 1.46 and 18.83 +/- 1.72) and MRT (3.68 +/- 0.19 and 4.34 +/- 0.14 h) for trimethoprim after i.m. and oral dosing, respectively. The absolute bioavailability (F) was 95.41% and 86.20% for sulfadiazine and 70.02% and 79.58% for trimethoprim after i.m. and oral administration, respectively.

The aim was to study the tolerability and plasma concentrations of pyrimethamine and sulfadiazine in children treated for congenital toxoplasmosis. Infants were diagnosed through the Danish Toxoplasma Neonatal Screening Programme, based on detection of toxoplasma-specific IgM- and/or IgA-antibodies on 3 mm blood spots collected from phenylketonuria [PKU cards (Guthrie cards)]. Toxoplasma-infected children received 3 months' continuous treatment with 50-100 mg/kg per day sulfadiazine in two separate administrations and 1 mg/kg per day pyrimethamine after a 1-day loading dose of 2 mg/kg, and folinic acid 7.5 mg was administered twice weekly. Blood cell counts and body weight were recorded during follow-up. The plasma concentrations of pyrimethamine and sulfadiazine were analysed in a subgroup of seven children, using high performance liquid chromatography with ultraviolet and mass spectrometric detection. Of 48 infants, 41 completed the treatment without change in schedule. Six infants had neutrophil counts below 0.5x10(9)/l, and one infant had an elevated bilirubin value. Twenty-nine children were tested by a series of neutrophil counts during treatment. The neutrophil count was

A method for the simultaneous determination of pyrimethamine, sulfadiazine and its metabolite N-acetyl-sulfadiazine in small plasma samples from neonates in treatment for congenital toxoplasmosis has been developed. In this method only 25 microl of plasma is used and a simple sample preparation based on protein precipitation and centrifugation provides highly reliable data as the recovery is about 100% and the precision is good. The analysis is performed using high performance liquid chromatography with UV and mass spectrometric (MS) detection. Pyrimethamine was found to give a linear response using MS detection in the range 0.02-5 microg/ml. Sulfadiazine and its metabolite N-acetyl-sulfadiazine were preferably analysed by UV at 269 nm in the concentration ranges 0.2-200 microg/ml for sulfadiazine and 0.2-50 microg/ml for N-acetyl-sulfadiazine.

Trimethoprim-sulfadiazine was administered to horses in a randomized, placebo controlled study to determine the effects of potentiated sulfonamides on thyroid function in normal horses. The treatment group included eight horses that received trimethoprim-sulfadiazine mixed with molasses orally at 30 mg/kg once daily for eight weeks. The control group included 8 horses that received an oral placebo (flour mixed with molasses) once daily for the same period. Thyroid function was evaluated prior to initiation of treatment and after 8 weeks of treatment. Serum concentrations of total and free triiodothyronine (T3), total and free thyroxine (T4), and thyroid stimulating hormone (TSH) were determined at rest and after a thyrotropin-releasing hormone (TRH) stimulation test. There was no detectable difference between treatment and control groups.

The pharmacokinetics of 2,000 mg of sulfadiazine administered twice daily (BID) versus those of 1,000 mg administered four times a day were compared in eight human immunodeficiency virus-infected patients. No differences in pharmacokinetic parameters were detected between the regimens. These data provide a pharmacokinetic rationale for BID dosing of sulfadiazine for the treatment and suppression of toxoplasmosis.

A method for the simultaneous determination of sulfadiazine and trimethoprim in plasma from Beagle dogs was developed and validated. Samples were deproteinized with acetonitrile and extracted with ethyl acetate. Sulfachloropyridazine and ormethoprim were used as internal standards for the sulfadiazine and trimethoprim analysis, respectively. The chromatography was carried out both on an LC-UV (liquid chromatography-ultraviolet detection) and ion-trap LC-MS(n) (liquid chromatography-mass spectrometric detection) instrument, operating in the positive APCI mode (atmospheric pressure chemical ionization). The purpose of this work was to compare the quantification results of both methods. Both the LC-UV and LC-MS-MS methods were validated for their linearity, accuracy, precision, limit of detection and limit of quantification, according to the requirements defined by the European Community. Calibration curves using plasma fortified between 0.1 and 1 microg/ml of sulfadiazine, 0.1 and 2 microg/ml of trimethoprim, 1 and 20 microg/ml of sulfadiazine showed a good linear correlation (r> or =0.9990, goodness-of-fit< or =8.4%). The results for the accuracy and precision at 1 microg/ml of sulfadiazine and trimethoprim and at 20 microg/ml of sulfadiazine fell within the ranges specified. The limits of quantification of both methods were 0.1 microg/ml. The limits of detection were 0.019 microg/ml of sulfadiazine and 0.024 microg/ml of trimethoprim for the LC-UV method, and 0.020 microg/ml of sulfadiazine and 0.062 microg/ml of trimethoprim for the LC-MS-MS method. The methods have been successfully applied in a pharmacokinetic study to determine the drug concentrations in plasma samples from dogs. A good correlation between the results of both methods was observed (R=0.9724, slope=1.0239, intercept=-0.2080 microg/ml for sulfadiazine and R=0.9357, slope=1.0433, intercept=0.0325 microg/ml for trimethoprim). The precision of both methods was also tested on the results of the same samples using an F-test (alpha=0.05), indicating that both methods did not differ in precision.

Sulfonamides and trimethoprim are chemotherapeutics that are extensively used in various animal species. Little information about the pharmacokinetics of these compounds in chickens exists in the literature. In this study, a new commercial formulation of sulfadiazine in combination with trimethoprim was administered both intravenously and orally, according to a crossover design, to healthy, 7-week-old broilers. The plasma concentrations of the drugs were determined by validated high-performance liquid chromatographic methods, and pharmacokinetic parameters were calculated. After intravenous or oral administration of trimethoprim (6.67 mg/kg body weight) and sulfadiazine (33.34 mg/kg body weight), both active substances were rapidly eliminated from the plasma. There was a mean half-life of 1.61 h for trimethoprim and 3.2 h for sulfadiazine. The apparent volumes of distribution (2.2 and 0.43 L/kg, respectively, indicated that the tissue distribution of trimethoprim was more extensive than that of sulfadiazine. The oral bioavailability was approximately 80% for both components.

The distribution of trimethoprim (TMP) and sulfadiazine (SDZ) into subcutaneously implanted noninfected tissue chambers was studied in healthy adult ponies. Six ponies were given an oral TMP/SDZ paste formulation at a dose of 5 mg/kg TMP and 25 mg/kg SDZ at 12 h intervals for 2 days in order to reach steady-state concentrations. Plasma concentrations and tissue chamber fluid (TCF) concentrations of both drugs were measured at regular intervals during a period commencing 24 h after the last oral administration. The peak concentration of TMP (mean +/- SD) was 2.92 +/- 0.86 microg/mL for plasma and 1.09 +/- 0.25 microg/mL for TCF. For SDZ, the mean peak concentration was 40.20 +/- 14.74 microg/mL for plasma and 23.48 +/- 5.84 microg/mL for TCF. TMP peak concentrations in plasma were reached at 3.17 +/- 03.48 h and those in TCF at 7.33 +/- 03.72 h. SDZ peak concentrations in plasma were reached at 1.83 +/- 02.04 h and those in TCF at 8.00 +/- 03.10 h. Concentrations of TMP and SDZ in TCF remained above the generally accepted breakpoint for susceptibility (0.5/9.5 for the TMP/SDZ combination) for 12 h. Therefore, in ponies oral administration of TMP/SDZ at a dose rate of 30 mg/kg given twice daily in the form of a paste should be appropriate for effective treatment of infections caused by susceptible bacteria.

A new method for simultaneous quantification of trimethoprim, sulfadiazine and N4-acetylsulfadiazine in plasma of broilers at levels down to 13-16 ng/ml has been developed. Samples were deproteinized with acetonitrile, defatted with hexane, and extracted with dichloromethane. Chromatographic analysis was carried out on a C18 column in the presence of tetrabutylammonium hydrogen sulfate, a competing base, while detection was performed at 240 nm for trimethoprim, and 270 nm for both sulfadiazine and N4-acetylsulfadiazine. Accuracy and precision data showed recoveries and relative standard deviation values better than 87.3% and 3.1%, respectively, for all three analytes. The good analytical characteristics of the method could allow limits of detection in the low ng/ml range to be realised. The method was successfully applied to determine drug concentrations in plasma samples from broilers administered a combination of sulfadiazine and trimethoprim.

Following the regimen used to treat equine protozoal myeloencephalitis, sulfadiazine (20 mg/kg) and pyrimethamine (1mg/kg) were administered orally once daily to 12 physically conditioned Thoroughbred horses for 4 consecutive days. The horses were randomly assigned to two test groups in a crossover design, with each horse serving as its own control. A stepwise exercise stress test was conducted to exhaustion. No effect on athletic performance was observed, and only marginal effects were noted in some hematologic and serochemical measurements, including decreased total white blood cell counts, red blood cell distribution width, total hemoglobin, serum sodium, and serum chloride. Serum folic acid concentration decreased significantly following sulfadiazine/pyrimethamine treatment.

Six healthy adult horses were given repeated administrations of trimethoprim/ sulfadiazine (TMP/SDZ) intravenously (i.v.) (2.5 mg/kg TMP and 12.5 mg/kg SDZ) and orally (p.o.) as a paste (5 mg/kg TMP and 25 mg/kg SDZ). Both formulations were given twice daily for 5 days, with a 3-week interval between i.v. and oral administration. The influence of the drug combination on the intestinal microflora was examined and the plasma concentrations, pharmacokinetic parameters and plasma protein binding were determined. There were no major changes in the bacterial intestinal flora and no clinical evidence of gastrointestinal disturbances following the i.v. and oral TMP/SDZ administration. An initial reduction in the number of coliform bacteria during the treatment was notable, though with no evident difference between i.v. and oral treatment. The minimum concentration during a dose interval at steady state (Cminss), the elimination half-life (t1/2beta) and the mean residence time (MRT) were significantly greater after oral administration compared to i.v. for both TMP and SDZ. The plasma protein binding was measured to be 20% for SDZ and 35% for TMP. Oral administration of TMP/SDZ in a dose of 30 mg/kg given twice daily in the form of paste appeared as a satisfactory method for obtaining plasma levels above MIC (minimum inhibitory concentration in vitro) values during the interdosing interval.

Twenty-six healthy female pigs weighing 19.5-33 kg were used in three separate experiments. The animals were fed individually twice a day. Trimethoprim/sulphadiazine (TMP/SDZ) formulation was added to feed in the amount of 6 mg/kg bw (TMP) and 30 mg/kg bw (SDZ). TMP and SDZ concentrations in blood plasma, muscles, liver and kidneys were measured. Pharmacokinetic parameters show that the absorption of TMP from the alimentary tract in pigs is faster than the absorption of SDZ, and the elimination of TMP is slower than that of SDZ. The absorption half-lives were 0.96 (TMP) and 2.24 h (SDZ), whereas elimination half-lives were 5.49 (TMP) and 4.19 h (SDZ). The observed TMP:SDZ ratios in blood plasma after multiple dose administration ranged from 1:11.4 to 1:23.2. One day after administration of the last dose of TMP/SDZ the plasma concentration ratio was 1:15.5, but in muscles, liver and kidneys it was much lower: 1:0.79, 1:0.14 and 1:1.53 respectively. The absolute TMP and SDZ tissue concentrations 1 day after the last multiple dose administration were very low (maximum TMP: 0.29 micrograms/g in liver; maximum SDZ: 0.23 micrograms/g in kidneys). Neither drug was detected in any tissue 8 days after the last administration of TMP/SDZ. Based on our results, it was concluded that there is no support for the TMP:SDZ pharmaceutical ratio 1:5 in oral formulations of these compounds for pigs. The administration oral TMP/SDZ formulations once a day may result in the absolute tissue concentrations of these drugs being too low for antibacterial activity. The withdrawal period for such an oral TMP/SDZ formulation for pigs (according to accepted guidelines in Europe for MRL of TMP < 0.05 mg/kg of tissue) should not be less than 5 days.

A high-performance liquid chromatographic method for the determination of sulfadiazine in human plasma and human urine was developed and validated. The method involves the acid extraction of drug and internal standard from plasma with ethyl acetate followed by evaporation and reconstitution in mobile phase. Urine samples were simply diluted with purified water. Recovery, linearity, intra- and inter-day variation of sulfadiazine were tested and found appropriate. The quantitation range was 0.0299-15.2 micrograms/ml for plasma samples and 0.578-148.8 micrograms/ml for urine samples. The method is suitable for the quantitation of sulfadiazine from pharmacokinetic studies.

The following metabolites of sulfadiazine (S) were isolated from monkey urine by preparative HPLC: 5-hydroxysulfadiazine (5OH), 4-hydroxysulfadiazine (4OH) and the glucuronide (5OHgluc) and sulfate conjugate of 5OH (5OHsulf). The compounds were identified by NMR, mass and infrared spectrometry and hydrolysis by beta-glucuronidase. The analysis of S, the hydroxymetabolites (4OH, 5OH) and conjugates N4-acetylsulfadiazine (N4), 5OHgluc and 5OHsulf in human and monkey plasma and urine samples was performed using reversed-phase gradient HPLC with UV detection. In plasma, S and N4 could be detected in high concentrations, whereas the other metabolites were present in only minute concentrations. In urine, S, the metabolites and conjugates were present. The limit of quantification of the compounds in plasma varies between 0.2 and 0.6 microgram/ml (S 0.31, N4 0.40, 4OH 0.20, 5OH 0.37, 5OHgluc 0.33 and 5OHsulf 0.57 microgram/ml). In urine it varies between 0.6 and 1.1 micrograms/ml (S 0.75, N4 0.80, 4OH 0.60, 5OH 0.80, 5OHgluc 0.80 and 5OHsulf 1.1 micrograms/ml). The method was applied to studies with healthy human subjects and Rhesus monkeys. The metabolites 5OH, 5OHgluc and 5OHsulf were present in Rhesus monkey and not in man. Preliminary results of studies of metabolism and pharmacokinetics in Rhesus monkey and man are presented.

The disposition of sulphadiazine (SDZ) and trimethoprim (TMP) was measured after intravenous and oral administration. Six healthy pigs weighing 17 to 34 kg received 20 mg kg-1 SDZ plus 4 mg kg-1 TMP intravenously, and 40 mg kg-1 SDZ plus 8 mg kg-1 TMP orally in both a fed and a fasted condition in a three-way cross-over design. After intravenous administration SDZ and TMP were present in plasma for 30 and 12 hours, respectively. The volume of distribution was 0.5 litre kg-1 bodyweight for SDZ and 1.8 litre kg-1 bodyweight for TMP. The oral bioavailabilities for SDZ and TMP in the fed pigs were 85 per cent and 92 per cent, and in the fasted pigs 89 per cent and 90 per cent, respectively. Although the presence of food did not affect the almost complete absorption of both drugs, it did prolong the absorption phase. Mean absorption time was nearly twice as long in the fed as in the fasted pig. Based on bioavailability and the resulting plasma concentrations it is concluded that the oral administration of SDZ and TMP was efficient in both the fed and fasted pigs.

Clean-up and high-performance liquid chromatographic methods for the simultaneous determination of sulphadiazine and trimethoprim in fish plasma and tissues have been developed. The average recovery of sulphadiazine varied from 74% in liver to 92% in plasma, whereas that of trimethoprim varied from 60% in liver to 97% in plasma. The sample pretreatment procedures were simple, selective and robust, having a limit of quantification of 250 ng/ml for trimethoprim and 50 ng/ml for sulphadiazine in plasma, 15 ng/g for sulphadiazine and 80 ng/g for trimethoprim in muscle, and 30 ng/g for sulphadiazine and 160 ng/g for trimethoprim in liver. The assay was tested on plasma from Atlantic salmon treated with Tribrissen.

Six healthy adult mixed breed dogs were each given 5 oral doses of trimethoprim (TMP)/sulfadiazine (SDZ) at 2 dosage regimens: 5 mg of TMP/kg of body weight and 25 mg of SDZ/kg every 24 hours (experiment 1) and every 12 hours (experiment 2). Serum and skin concentrations of each drug were measured serially throughout each experiment and mean serum concentrations of TMP and SDZ were determined for each drug for 24 hours (experiment 1) and 12 hours (experiment 2) after the last dose was given. In experiment 1, mean serum TMP concentration was 0.67 +/- 0.02 micrograms/ml, and mean skin TMP concentration was 1.54 +/- 0.40 micrograms/g. Mean serum SDZ concentration was 51.1 +/- 12.2 micrograms/ml and mean skin SDZ concentration was 59.3 +/- 9.8 micrograms/g. In experiment 2, mean serum TMP concentration was 1.24 +/- 0.35 micrograms/ml and mean skin TMP concentration was 3.03 +/- 0.54 micrograms/g. Mean serum SDZ concentration was 51.6 +/- 9.3 micrograms/ml and mean skin SDZ concentration was 71.1 +/- 8.2 micrograms/g. After the 5th oral dose in both experiments, mean concentration of TMP and SDZ in serum and skin exceeded reported minimal inhibitory concentrations of TMP/SDZ (less than or equal to 0.25/4.75 micrograms/ml) for coagulase-positive Staphylococcus sp. It was concluded that therapeutically effective concentrations in serum and skin were achieved and maintained when using the manufacturer's recommended dosage of 30 mg of TMP/SDZ/kg (5 mg of TMP/kg and 25 mg of SDZ/kg) every 24 hours.

Quantitative determination of tetroxoprim and sulphadiazine in serum and urine was performed using reversed phase high performance liquid chromatography. Protein precipitation using 10% perchloric acid was utilized for purification of serum samples while urine samples were diluted prior to analysis. The mobile phase consisted of triethylammonium acetate buffer (85%), acetonitrile (12%) and methanol (3%), with a final pH of 4.2. The eluent was monitored at 280 nm. Benzoic acid was used as an internal standard. Standardization, validation and application of the method is described.

Trimethoprim (TMP) was administered in combination with either sulphadiazine or sulphadimidine to broilers, and plasma concentrations were determined simultaneously by newly developed thin-layer and/or high-performance liquid-chromatographic procedures, which also allowed quantification of the N4-acetyl metabolites of the sulphonamides. After i.v. injection of TMP (20 mg/kg body wt) and sulphadiazine (100 mg/kg body wt), both compounds were rapidly eliminated from plasma with half-lives of 1 and 2.7 h, respectively. Apparent volumes of distribution (3.3 and 0.96 l/kg, respectively) indicated that the tissue distribution of TMP was more extensive than that of the sulphonamide. After oral administration of the same dosages, elimination appeared to be slower compared to the i.v. injection, but this was obviously related to delayed absorption. Bioavailability after oral administration was approximately 100% of sulphadiazine, but only about 60% for TMP. Oral dosing of TMP in combination with sulphadimidine yielded similar maximum plasma concentrations of both compounds to those obtained with the combination of TMP with sulphadiazine, but the plasma concentration decline of sulphadimidine appeared to be more rapid than that of sulphadiazine after oral administration. During prolonged administration of different dosages of TMP-sulphadiazine combinations via drinking water, only low plasma concentrations were attained by the recommended dosage of the combination. Up to 10-fold higher dosages were tolerated by the animals without side-effects. In view of the fact that the sensitivity of bacterial strains to TMP-sulphonamide combinations differs widely, the plasma concentrations determined in the present study during prolonged drinking-water medication with different dosages of a TMP-sulphadiazine combination can be used to select effective doses for treatment of different poultry diseases.

Systemic absorption of water-soluble and water-insoluble drugs through human burn wounds was compared. Serum levels of sulphadiazine were estimated after application of silver sulphadiazine (water-insoluble) cream, sulphadiazine (water-insoluble) cream and sodium sulphadiazine (water-soluble) cream. It was found that the absorption of sodium sulphadiazine was greater than that of sulphadiazine or silver sulphadiazine.

One percent silver sulfadiazine has been commonly used as a topical antimicrobial agent after a burn injury. Incidence of burn wound colonization by Staphylococcus aureus in patients treated with silver sulfadiazine has spurred research for other agents. A topical preparation that contains zinc and sulfadiazine (Zad-G) was evaluated for in vitro antibacterial spectrum and in vivo efficacy. Muscle biopsy specimens of rats treated with Zad-G appear to have fewer colonies of S. aureus than groups treated with silver sulfadiazine. Topical therapy with Zad-G for patients with burns was comfortable, reduced wound infection, and was comparable to therapy with silver sulfadiazine. A topical Zad-G preparation that contains zinc sulfadiazine appears to be an effective alternative to silver sulfadiazine in the treatment of burn wounds.

Elimination kinetics determined by a timed plasma concentration curve on chloramphenicol, antipyrine, acetaminophen and sulphadiazine showed that plasma half-life was increased and elimination rate constant was diminished in malnourished children compared to those with normal nutrition. Area under the curve (AUC) was increased. Decreased urinary excretion of metabolites of chloramphenicol and sulphadiazine in malnourished children suggested an alteration in biotransformation. These findings were supported by a significant increase in steady-state levels of chloramphenicol and phenobarbitone in malnourished patients receiving drugs for therapy. In a subhuman primate animal model (young rhesus monkey) which was akin to the human situation both for protein energy malnutrition and for drug pharmacokinetics it was observed that hepatic aminopyrine demethylase and chloramphenicol glucuronyl transferase activity was diminished. Thus drugs metabolised by the liver apparently clear at a slower pace in malnourished children. Therapy needs to be modified appropriately to achieve therapeutic response and avoid toxicity. Hepatotoxicity monitoring of antitubercular therapy with isoniazid and rifampicin was found to be 3 times higher in malnourished children. The acetylator status of the child did not correlate with hepatotoxicity. The majority of the children were slow acetylators. AUC of isoniazid was higher in malnourished children.

The effect of molecular structure on the drug disposition and protein binding in plasma, the urinary recovery, and the renal clearance of sulphamerazine (SMR), sulphadiazine (SDZ), and sulphadimidine (SDM) and their N4-acetyl and hydroxy derivatives were studied in pigs. Following IV administration of SDM, SMR and SDZ, their mean elimination half-lives were 12.4 h, 4.3 h and 4.9 h respectively. The plasma concentrations of parent sulphonamide were higher than those of the metabolites, and ran parallel. The acetylated derivatives were the main metabolites; traces of 6-hydroxymethylsulphamerazine and 4-hydroxysulphadiazine were detected in plasma. The urine recovery data showed that in pigs acetylation is the major elimination pathway of SDM, SMR and SDZ; hydroxylation became more important in case of SMR (6-hydroxymethyl and 4-hydroxy derivatives) and SDZ (4-hydroxy derivatives) than in SDM. In pigs methyl substitution of the pyrimidine side chain decreased the renal clearance of the parent drug and made the parent compound less accessible for hydroxylation. Acetylation and hydroxylation speeded up drug elimination, because their renal clearance values were higher than those of the parent drug.

The binding of sulfadiazine in the plasma of normal and uremic subjects was measured by means of an ultrafiltration technique. Patients with uremia had reduced binding of sulfadiazine due to decreased albumin-binding capacity. No conclusive evidence was found to suggest that reduced drug binding in uremia is caused by competing metabolites. Studies of purified normal and uremic albumin revealed differences in amino acid composition and variations in the protein content of the two albumin bands found on isoelectric focusing. It is suggested that decreased drug binding in uremia may be at least partly due to altered albumin composition.

A total of 60 clinical isolates of Paracoccidioides brasiliensis were tested for susceptibility to sulfadiazine and sulfadimethoxyne by the agar dilution technique. A modification of the Mueller-Hinton medium was devised which gave good growth of the yeast form. The minimum inhibitory concentrations for only 51.6% of the isolates were in the range of the recommended blood serum concentration (50 micrograms/ml). For 6 to 8% of the isolates, the minimum inhibitory concentrations were above 200 micrograms of both sulfadiazine and sulfadimethoxyne per ml. A significant decreases in susceptibility was demonstrated for one isolate obtained from a patient relapsing during sulfonamide therapy.

Two fasted and 2 fed horses were dosed orally with a combined trimethoprim and sulfadiazine paste formulation at a dose of 35 mg (1:5 combined active ingredients)/kg. Serum concentrations of each drug were determined periodically for 3 consecutive days for the 4 horses. The extent and rate of absorption for trimethoprim were variable, but peak serum concentrations occurred generally within 3 hours; sulfadiazine absorption was slower, reaching peak concentrations by 6 hours. Fasting did not have a consistent effect on the serum concentration profiles for either drug. Both drugs achieved serum concentrations that equaled or exceeded the minimum inhibitory concentrations necessary to inhibit the growth of certain pathogens common to the horse. Thus, the paste formulation provides an effective means of dose administration of horses.

The bioavailability of seven commercial trisulfapyrimidine suspensions was studied in 14 adult male volunteers. Fifteen blood samples were collected over a 48-hr period following administration of a 1-g dose of each suspension. Serum was assayed for each component (sulfadiazine, sulfamerazine, and sulfamethazine) by high-pressure liquid chromatography. Analysis of variance indicated several significant differences among the seven commercial preparations with respect to Cmax Tmax, and AUC for sulfadiazine, sulfamerazine, and sulfamethazine, The in vitro behavior of each suspension was then studied by the paddle method of the Food and Drug Administration. A 0.5-ml sample was introduced into 900 ml of hydrochloric acid (2.2 x 10(-4) M) at 37 degree and dissolved using a paddle speed of 25 rpm. Samples withdrawn at 15 and 30 min were analyzed by high-pressure liquid chromatography, and the percent of sulfadiazine, sulfamerazine, and sulfamethazine was calculated. Significant correlation was obtained between an in vivo parameter (Cmax for sulfadiazine) and an in vitro parameter (percent sulfadiazine dissolved in 30 min). Results indicate that this method is suitable for the in vitro screening of trisulapyrimidine suspensions.

A four-way crossover sulfadiazine bioavailability study was conducted in 16 normal healthy male volunteers. The subjects were divided into groups of eight. Each group received four different oral dosage forms of sulfadiazine at 1-week intervals: a solution as a reference, a suspension, and two different tablets. All dosage forms were equivalent to 500 mg of sulfadiazine. Blood samples were obtained at 0, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 25.0, 33.0, and 49.0 hr. Analysis of variance indicated no statistically significant difference (p more than 0.05) between the dosage forms in terms of area under the plasma level--time curve, peak plasma concentration, and time of peak plasma concentration. In both groups, there were differences between products at isolated sampling times. It was concluded that the four tablet formulations of sulfadiazine exhibited bioavailability characteristics equivalent to those of the solution and the suspension.

Influence of alloxan induced metabolic disorder on the biodisposition kinetics of a weakly acidic drug sulphadiazine was investigated in rabbits. In 12 rabbits, mean +/- SD blood pH was 7.45 +/- 0.05, plasma glucose 123 +/- 10.6 mg%, plasma total lipids 336 +/- 124 mg% and plasma urea 36 +/- 6 mg%. After treatment with 150 mg/kg alloxan intravenously the blood pH was 7.20 +/- 0.06, plasma glucose 393 +/- 80.3, total lipids 532 +/- 181 and plasma urea was 48 +/- 10 mg%. Disposition kinetics showed that the plasma concentration of sulphadiazine was significantly (P less than 0.01) higher in normal condition when compared with that of metabolically altered. The zero-time plasma concentration was significantly (P less than 0.01) higher, apparent volume of distribution and total body clearance were significantly (P less than 0.01) lower in the normal than in the metabolically altered condition of rabbits. Elimination rate constant and the half-life did not reveal any significant difference in the normal and metabolically altered conditions. These studies demonstrate that the clinical biochemical conditions can influence the disposition kinetics and fate of weakly acid, and possibly of the weakly basic drugs. Therefore, the therapeutic standards of the drugs need be verified in the condition in which the drugs are to be employed clinically.

The uptake of sulfonamides and sulfonamide potentiators by plasma albumin, red blood cells and hemoglobin of man, ox, rabbit and mouse has been determined. From the figures obtained the distribution of these compounds between cells, macromolecules and aqueous phases of blood has been calculated. In most cases more than 50% of a total sulfonamide in blood is bound to plasma albumin. The time necessary for establishment of concentration equilibrium of the drugs investigated between erythrocytes and surrounding medium varies between a few seconds and several minutes, differences between the species being encountered. Hemoglobin binding of the drugs is much smaller than albumin binding. Nevertheless, drug concentration within the erythrocytes is generally higher than in the surrounding medium.

A high-performance liquid chromatographic method for the determination of acetazolamide in whole blood, plasma, and urine was developed. Samples of biological fluids containing various concentrations of acetazolamide were spiked with the internal standard, sulfadiazine. Samples were then mixed with a 50% ammonium sulfamate solution. Whole blood samples were heated for 25 s in boiling water. All samples were extracted with ethyl acetate; a phosphate buffer (pH 8.0) was used to wash the extracts. Acetazolamide was back-extracted into a glycine buffer (pH 10.0), which was then washed with ether. Separation of acetazolamide and internal standard from other biological constituents was achieved on a 10-micron C18 reverse-phase column using an acetonitrile-methanol-acetate buffer (pH 4.0). The eluant was monitored at 254 nm. All calibration curves were linear, and the results from reproducibility studies were excellent. Application of the method to human pharmacokinetic studies was demonstrated.

A normal-phase high-performance liquid chromatographic method was developed to determine the concentration of timethoprim, sulfadiazine and its N4-acetyl derivative in human serum and urine. The unchanged compounds and the metabolite are extracted in organic solvent by a single extraction. The method is accurate and sensitive and suited for pharmacokinetic studies in man.

1. The kinetics of sulphadiazine were studied in well-nourished and under-nourished subjects. 2. The metabolic clearance rate of a single dose of sulphadiazine given either orally or intravenously was faster in under-nourished subjects. 3. The plasma protein binding of the drug was found to be reduced in under-nourished subjects. 4. Blood concentrations (48 h and 72 h) of sulphadiazine tended to be low in the under-nourished as compared with well-nourished subjects after administration of multiple doses of the drug. 5. It is concluded that a revision in the dosage schedule may not be necessary in the treatment of under-nourished subjects with sulphadiazine, since the blood concentrations were higher than the reporte d minimum to combat infection.

Following a single dose of co-trimoxazole or co-tetroxazine, the plasma and urine levels of intact trimethoprim (TMP) and sulphamethoxazole (SMZ) and of tetroxoprim and sulphadiazine (SDZ) were determined in six geriatric patients in a cross-over design by high pressure liquid chromatography. The pharmacokinetic analysis showed a plasma elimination half-life in the terminal phase of 10.39 h for TMP, 11.79 h for SMZ, 6.55 h for TXP and 10.46 h for SDZ. The resulting distribution volumes Vd beta and total plasma clearance values corresponded with the data obtained in young patients or volunteers. Recovery in urine, measured for up to 96 h, was 49.2% (TMP), 19.8% (SMZ), 57.03% (TXP) and 61.1% (SDZ). In contrast to young volunteers, geriatric patients experienced a slight prolongation of renal excretion for both sulphonamides. In this group of patients the renal clearance was 2.42 ml/min for SMZ and 10.7 ml/min for SDZ.

1. Following intravenous administration of sulphadiazine (2-sulphailamido-pyrimidine) to goats, unchanged sulphadiazine comprised the major part of the total sulphonamide in blood plasma, milk and urine samples. 2. Relatively small amounts of N4-acetysulphadiazine were excreted in milk and urine. The amount of conjugated metabolites in urine was small, but was comparatively large in the milk samples. 3. A new metabolite, 2-sulphanilamido-4-hydroxyprimidine, which comprised about 15% of the total sulphonamide in urine was isolated.

Two HPLC methods for determination of tetroxoprim and sulphadiazine in pharmaceutical dosage forms and in biological fluid are reported. Both methods show good linearity, precision, accuracy and reproducibility. The serum levels and urinary excretion of tetroxoprim and sulphadiazine in man, after oral administration of two different syrup formulations, are reported. Tetroxoprim embonate, an insoluble salt very useful for obtaining a suspension with good palatability, shows a bioavailability not statistically different from that of tetroxoprim base. Sulphadiazine shows the same bioavailability in the two syrups.

The binding of 3 drugs to serum proteins of patients with chronic hepatic disease has been studied by an ultrafilitration technique, and compared to that of normal subjects. The binding of phenylbutazone was reduced in all patients, salicylate in patients with inactive liver disease and sulphadiazine in patients whose disease was active. Analysis of binding data showed a real reduction in the capacity of albumin to bind the drugs in the majority of patients. Addition of bilirubin to normal plasma caused a reduction in sulphadiazine binding, but had no effect on the binding of salicylate or phenylbutazone. The possible causes of this reduction in binding are discussed.

The tarsocrural joints of 11 horses were inoculated with 1.2 to 2.16 x 10(6) viable Staphylococcus aureus organisms susceptible to a trimethoprim-sulfadiazine (TMP-SDZ) combination with minimal inhibitory concentration (MIC) of 0.25 micrograms of TMP/ml and 4.75 micrograms of SDZ/ml. Antimicrobial treatment consisted of oral administration of a TMP-SDZ combination--30 mg/kg of body weight given once daily (group-1 horses) or 60 mg/kg given as 30 mg/kg every 12 hours (group-2 horses). Paired serum and synovial fluid samples were obtained before intra-articular inoculation with the S aureus, after inoculation with S aureus but before antimicrobial treatment, and after inoculation at various hourly intervals after oral administration of the TMP-SDZ combination. The TMP-SDZ combination was administered daily in the 2 dosages for 21 days. Samples were collected after day 3 of repetitive drug administration so that drug steady-state concentration would have been achieved. Serum and synovial fluid samples were analyzed for TMP and SDZ concentrations. Administration of the TMP-SDZ combination at a dosage of 30 mg/kg once daily was not effective in maintaining TMP or SDZ concentrations above the MIC of TMP-SDZ for the S aureus (0.25 and 4.75 micrograms/ml for TMP and SDZ, respectively) in the infected synovial fluid or in maintaining adequate TMP concentration in the serum. The alternative use of the TMP-SDZ combination at a dosage of 60 mg/kg given as 30 mg/kg every 12 hours was effective in maintaining serum and synovial fluid concentrations of TMP and SDZ that were greater than the MIC for the infective organism.(ABSTRACT TRUNCATED AT 250 WORDS)

Previous metabolic depletion studies of 14C-sulfadiazine (SDZ) in the neonatal calf led to identification of two novel metabolites, 2-benzenesulfonamidopyrimidine (desNH2SDZ) and 2-benzenesulfonamido-4-hydroxypyrimidine. The novelty of the biotransformation prompted examination of mechanisms for the reductive deamination of SDZ in vivo. In subsequent work, it was found that neonatal calves did not consistently convert SDZ to desNH2SDZ; however, calves that were treated simultaneously with nitrite did. Further, when SDZ was given orally to guinea pigs, whose diet is high in nitrate and who demonstrate the capacity to reduce nitrate to nitrite in the oral cavity, SDZ was transformed to desNH2SDZ. Rats did not reductively deaminate SDZ even if they consumed a diet high in nitrate for two weeks prior to treatment with SDZ. However, they did so when nitrite was added to their diet. These observations strongly suggest that reductive deamination of sulfonamides is dependent on the ingestion of nitrite or the reduction of dietary nitrate to nitrite. This reduction of nitrate to nitrite proceeds in the oral cavity, presumably via microflora residing there.

The binding of salicylate, sulphadiazine and phenylbutazone to plasma proteins has been studied in young and elderly subjects. Elderly patients had significantly reduced concentrations of plasma albumin, compared with subjects under 40 years of age. Sifnificant increases in free levels of all three drugs were found in elderly patients receiving multiple drug therapy, and a correlation obtained with the number of drugs being taken. It is suggested that because of their low albumin levels, elderly patients may be more susceptible to the effects of multiple drug therapy on drug binding. The clinical implications of these observations are discussed.