Sulfadiazine pharmacokinetics in grass carp (Ctenopharyngodon idellus) receiving oral and intravenous administrations.

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 (Kα ), the absorption half-life (t1/2 Kα ), the elimination rate constant (Ke ), the elimination half-life (t1/2Ke ), and the area under concentration-time profile (AUC0-∞ ) 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 (ß), the distribution half-life (t1/2α ), the elimination half-life (t1/2ß ), the apparent distribution volume (VSS ), the total clearance (CL), and AUC0-∞ 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.

Sulfadiazine plasma concentrations in women with pregnancy-acquired compared to ocular toxoplasmosis under pyrimethamine and sulfadiazine therapy: a case-control study.

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.

Voltammetric sensor based on carbon paste electrode modified with molecular imprinted polymer for determination of sulfadiazine in milk and human serum.

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%.

A novel chemiluminescence quenching method for determination of sulfonamides in pharmaceutical and biological fluid based on luminol-Ag(III) complex reaction in alkaline solution.

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.

Pharmacokinetics and bioavailability of sulfadiazine and trimethoprim following intravenous, intramuscular and oral administration in ostriches (Struthio camelus).

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.

Treatment of infants with congenital toxoplasmosis: tolerability and plasma concentrations of sulfadiazine and pyrimethamine.

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

Simultaneous determination of pyrimethamine, sulfadiazine and N-acetyl-sulfadiazine in plasma for monitoring infants in treatment of congenital toxoplasmosis.

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.

Effects of trimethoprim-sulfadiazine on thyroid function of horses.

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.

Plasma pharmacokinetics of sulfadiazine administered twice daily versus four times daily are similar in human immunodeficiency virus-infected patients.

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.

Pharmacokinetics and oral bioavailability of sulfadiazine and trimethoprim in broiler chickens.

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.

Comparison of a liquid chromatographic method with ultraviolet and ion-trap tandem mass spectrometric detection for the simultaneous determination of sulfadiazine and trimethoprim in plasma from dogs.

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.

Distribution of orally administered trimethoprim and sulfadiazine into noninfected subcutaneous tissue chambers in adult ponies.

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.

Effect of sulfadiazine and pyrimethamine on selected physiologic and performance parameters in athletically conditioned thoroughbred horses during an incremental exercise stress test.

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.

New simple liquid chromatographic method for the determination of trimethoprim, sulfadiazine and N4-acetylsulfadiazine in plasma of broilers.

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.

Repeated administration of trimethoprim/sulfadiazine in the horse--pharmacokinetics, plasma protein binding and influence on the intestinal microflora.

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.

A study of the pharmacokinetics and tissue residues of an oral trimethoprim/sulphadiazine formulation in healthy pigs.

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.

Improved determination of sulfadiazine in human plasma and urine by high-performance liquid chromatography.

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.

Isolation, identification and determination of sulfadiazine and its hydroxy metabolites and conjugates from man and rhesus monkey by high-performance liquid chromatography.

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.