LC-MS/MS methods for sulfadimethoxine and ormetoprim analysis in feed and fish fillet and a leaching study for feed after alternative procedures for the incorporation of drugs.

This paper describes the method development for sulfadimethoxine (SDM) and ormetoprim (OMP) quantitation in fish feed and fish fillet employing LC-MS/MS. In order to assess the reliability of the analytical method, valuation was undertaken as recommended by guidelines proposed by the Brazilian Ministry of Agriculture. The calibration curve for the quantification of both drugs in feed showed adequate linearity (r > 0.99), precision (CV < 12%) and trueness ranging from 97% to 100%. The method for the determination of SDM and OMP residues in fish fillet involved a simple sample preparation procedure that had adequate linearity (r > 0.99), precision (CV < 16%) and trueness around 100%, with CCα < 100.2 ng g-1 and CCß < 100.4 ng g-1. With a goal of avoiding the risk of drug leaching from feed into the aquatic environment during fish medication via the oral route, different procedures for drug incorporation into feed were evaluated. Coating feed pellets with ethyl cellulose polymer containing the drug showed promising results. In this case, medicated feed released drugs to water at a level below 6% when the medicated feed stayed in the water for up to 15 min.

Synthesis of sulfadimethoxine based surfactants and their evaluation as antitumor agents.

AIM OF THE STUDY: Synthesized CO (II) and Pt (II) of sulfadimethoxine. These compounds were tested for potential antitumor activity against two of human tumor cell lines, colon carcinoma cell line [Hct116], and breast carcinoma cell line MCF7. MATERIALS AND METHODS: The structures of the resulting compounds have been investigated by elemental, FT-IR and H 1 NMR analyzes to insure the purity and confirmed the structures of them. The surface properties studies and octanol/water partition coefficients, Po/w were measured. RESULTS: The synthesized compounds exhibit biological activities with the lowest log Po/w and critical micelle concentration (CMC) values. In addition, in this article we provide an insight into this subject in order to increase the drug bioavailability. Inhibitory activity against colon carcinoma cells was detected for Pt and cobalt ion complex with IC50 = 4.5, 2.2 µg and against breast carcinoma cells IC50 = 18.2, 5.7 µg, respectively. SUMMARY: The main goal of cancer therapy is to attain the maximum therapeutic damage of tumor cells in combination with a minimum concentration of the drug. This can be achieved in principle via selective antitumor preparations, the cytostatic effects of which would be restricted within tumor tissue. While 100% selectivity may be impractical, the achievement of reasonably high selectivity seems to be a feasible aim. Platinum and cobalt complex surfactants in our research affect tumor tissue at a very low concentration at values lower than their CMC values; this indicate that the sulfadimethoxine complexes merit further investigation as potential antitumor drugs.

Multifunctional network-structured film coating for woven and knitted polyethylene terephthalate against cardiovascular graft-associated infections.

Multifunctional network-structured polymeric coat for woven and knitted forms of crimped polyethylene terephthalate PET graft was developed to limit graft-associated infections. A newly synthesized antibacterial sulfadimethoxine polyhexylene adipate-b-methoxy polyethylene oxide (SD-PHA-b-MPEO) di-block copolymer was employed. Our figures of merit revealed that the formed coat showed a porous topographic architecture which manifested paramount properties, mostly bacterial anti-adhesion efficiency and biocompatibility with host cells. Compared to untreated grafts, the coat presented marked reduction of adhered Gram-positive Staphylococcus epidermidis previously isolated from a patient's vein catheter by 2.6 and 2.3 folds for woven and knitted grafts, respectively. Similarly, bacterial anti-adhesion effect was observed for Staphylococcus aureus by 2.3 and 2.4 folds, and by 2.9 and 2.7 folds for Gram-negative Escherichia coli for woven and knitted grafts, respectively. Additionally, adhesion and growth characteristics of L929 cells on the modified grafts revealed no significant effect on the biocompatibility. In conclusion, coating of PET with (SD-PHA-b-MPEO) is a versatile approach offers the desired bacterial anti-adhesion effect and host biocompatibility.

Resistance gene transfer during treatments for experimental avian colibacillosis.

An experiment was conducted in animal facilities to compare the impacts of four avian colibacillosis treatments-oxytetracycline (OTC), trimethoprim-sulfadimethoxine (SXT), amoxicillin (AMX), or enrofloxacin (ENR)-on the susceptibility of Escherichia coli in broiler intestinal tracts. Birds were first orally inoculated with rifampin-resistant E. coli strains bearing plasmid genes conferring resistance to fluoroquinolones (qnr), cephalosporins (bla(CTX-M) or bla(FOX)), trimethoprim-sulfonamides, aminoglycosides, or tetracyclines. Feces samples were collected before, during, and after antimicrobial treatments. The susceptibilities of E. coli strains were studied, and resistance gene transfer was analyzed. An increase in the tetracycline-resistant E. coli population was observed only in OTC-treated birds, whereas multiresistant E. coli was detected in the dominant E. coli populations of SXT-, AMX-, or ENR-treated birds. Most multiresistant E. coli strains were susceptible to rifampin and exhibited various pulsed-field gel electrophoresis profiles, suggesting the transfer of one of the multiresistance plasmids from the inoculated strains to other E. coli strains in the intestinal tract. In conclusion, this study clearly illustrates how, in E. coli, "old" antimicrobials may coselect antimicrobial resistance to recent and critical molecules.

Inhibitory effects of aminoguanidine on thyroid follicular carcinoma development in inflamed capsular regions of rats treated with sulfadimethoxine after N-bis(2-hydroxypropyl)nitrosamine-initiation.

We have reported that thyroid capsular thickening with inflammation induced by an antithyroidal agent, sulfadimethoxine (SDM), might play a role in the development of invasive follicular carcinomas in rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). Inducible nitric oxide synthase (iNOS) expressed in the inflamed capsular regions further appeared to be implicated in the tumor progression. In the present study, the effects of an iNOS inhibitor, aminoguanidine (AG), on thyroid carcinogenesis were examined. F344 male rats were treated with SDM in drinking water (0.1%) with or without concomitant dietary administration of AG (0.2%) for 4 and 10 weeks after subcutaneous injection of DHPN at 2800 mg/kg bodyweight. At week 4, thyroid capsular thickening with inflammation was observed and iNOS-positive foci were found in the inflamed regions. In addition, single-strand DNA-positive inflammatory cells were scattered among neighboring follicular cells, indicating some cellular damage, at least partly in association with iNOS induction. Concurrent dietary administration of AG with SDM treatment slightly decreased the number of single-strand DNA-positive cells but did not alter the incidence and multiplicity of iNOS-positive foci in the inflamed capsular regions at week 4. At week 10, however, invasive follicular carcinomas predominantly arose in the thickened capsule in the DHPN-SDM-treated rats, and AG administration decreased (P < 0.05) their multiplicity. The carcinoma cells were partly positive for iNOS. These results thus suggested that iNOS induction in both inflammatory and tumor cells might play pivotal roles in tumor progression in this DHPN-SDM rat model.

Cellular distributions of molecules with altered expression specific to thyroid proliferative lesions developing in a rat thyroid carcinogenesis model.

To identify differentially regulated molecules related to early and late stages of tumor promotion in a rat two-stage thyroid carcinogenesis model by an antithyroid agent, sulfadimethoxine, microarray-based microdissected lesion-specific gene expression profiling was carried out. Proliferative lesions for profiling were divided into two categories: (i) focal follicular cell hyperplasias (FFCH) and adenomas (Ad) as early lesions; and (ii) carcinomas (Ca) as more advanced. In both cases, gene expression was compared with that in surrounding non-tumor follicular cells. Characteristically, upregulation of cell cycle-related genes in FFCH + Ad, downregulation of genes related to tumor suppression and transcription inhibitors of inhibitor of DNA binding (Id) family proteins in Ca, and upregulation of genes related to cell proliferation and tumor progression in common in FFCH + Ad and Ca, were detected. The immunohistochemical distributions of molecules included in the altered expression profiles were further examined. In parallel with microarray data, increased localization of ceruloplasmin, cyclin B1, and cell division cycle 2 homolog A, and decreased localization of poliovirus receptor-related 3 and Id3 were observed in all types of lesion. Although inconsistent with the microarray data, thyroglobulin immunoreactivity appeared to reduce in Ca. The results thus suggest cell cycling facilitation by induction of M-phase-promoting factor consisting of cyclin B1 and cell division cycle 2 homolog A and generation of oxidative responses as evidenced by ceruloplasmin accumulation from an early stage, as well as suppression of cell adhesion involving poliovirus receptor-related 3 and inhibition of cellular differentiation regulated by Id3. Decrease of thyroglobulin in Ca may reflect dedifferentiation with progression.

Depression of T cell-mediated immunity reduces sulfadimethoxine-induced capsular inflammation and inhibits associated development of invasive thyroid follicular cell carcinomas in rats.

We previously demonstrated that thyroid capsular inflammation induced by continuous treatment with the antithyroidal agent sulfadimethoxine is associated with development of invasive follicular cell carcinomas in rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). The inflammatory changes are characterized by large numbers of macrophages and lymphocytes as well as fibroblasts and we hypothesized that it might be enhanced by interplay between macrophages and T cells. To clarify this hypothesis, a comparative study was conducted between athymic nude (rnu/rnu) rats and euthymic (rnu/+) littermates initiated with DHPN (2800 mg/kg, s.c.) followed by sulfadimethoxine treatment in drinking water (0.1%) for 10 weeks. In rnu/+rats, marked capsular thickening with inflammation was induced along with invasive follicular cell carcinomas (2.8 +/- 1.3/rat). In rnu/rnu rats, limited fibrous capsular thickening was noted with or without minimal inflammatory change, and the multiplicity of invasive carcinomas was significantly lower (1.1 +/- 1.0/rat, P < 0.01). Inducible nitric oxide synthase expression in the inflamed lesions was detected in three of 10 rnu/+rats but in none of the rnu/rnu animals. The results thus suggest that development of invasive carcinomas is enhanced by capsular inflammation mediated by T cells, and inducible nitric oxide synthase induction may play a role in tumor progression.

Sequential analysis of development of invasive thyroid follicular cell carcinomas in inflamed capsular regions of rats treated with sulfadimethoxine after N-bis(2-hydroxypropyl)nitrosamine-initiation.

A 2-stage thyroid follicular carcinogenesis model in rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN) is widely used to detect modifying effects of chemicals on thyroid carcinogenesis. A number of goitrogens are known to strongly promote carcinogenesis, and the carcinomas often originate adjacent to the thyroid capsule and show invasive growth into the capsule or adjacent tissues. To clarify mechanisms of progression to invasive carcinomas, we sequentially evaluated histopathological and immunohistochemical characteristics of thyroids in male F344 rats treated with sulfadimethoxine (SDM, 0.1% in drinking water) for 0-10 weeks beginning 1 week after DHPN initiation (2800 mg/kg body weight, single s.c. injection). In DHPN-SDM-treated rats, multiple focal hyperplasias and adenomas developed in thyroid follicular parenchyma at weeks 4 to 6. Apart from the proliferative lesions, capsular thickening with inflammatory cell infiltration, mainly consisting of macrophages, and migration of follicular epithelium into the capsule were also observed. Focal hyperplasias/adenomas adjacent to the capsule progressively developed to invasive carcinomas at weeks 6 to 10. In thyroid parenchyma, malignant lesions were seldom observed. With SDM-treatment alone, although no neoplastic lesions were observed, capsular thickening with inflammation and epithelial migration resulted in intracapsular residual follicles. Intracapsular residual follicular cells as well as invasive and intrathyroidal carcinoma cells generally showed increased cell proliferative activity, coincidental with cytoplasmic/nuclear positivity for beta-catenin. These results suggested that beta-catenin activation related to capsular inflammation may play a role in development of invasive carcinomas but is insufficient for tumor formation by itself. Whether this is associated with mutations in the beta-catenin gene remains to be clarified.

Pharmacokinetics of sulfadimethoxine and ormetoprim in a 5:1 ratio following intraperitoneal and oral administration, in the hybrid striped bass (Morone chrysops x Morone saxitalis).

Selected pharmacokinetic parameters for sulfadimethoxine and ormetoprim, administered in a 5:1 ratio, via the oral and intraperitoneal (i.p.) routes were determined in the hybrid striped bass (Morone chrysops x Morone saxitalis). Plasma concentrations of both drugs were determined by high-performance liquid chromatography. A first-order one-compartment model adequately described plasma drug disposition. The elimination half-lives for sulfadimethoxine following i.p. and oral administration were 26 and 10.5 h, respectively. The half-lives for ormetoprim administered via i.p. and oral routes were 7.5 and 3.9 h, respectively. Cmax for sulfadimethoxine via the i.p. and oral routes were calculated to be 27.7 (+/-9.0) microg/mL at 3.6 h and 3.2 (+/-1.2) microg/mL at 1.2 h, respectively. Cmax for ormetoprim via the i.p. route was calculated to be 1.2 (+/-0.5) microg/mL at 9.1 h and 1.58 (+/-0.7) microg/mL at 5.7 h for the oral route. The oral availability of sulfadimethoxine relative to the i.p. route was 4.6%, while the oral availability of ormetoprim relative to the i.p. route was 78.5%. Due to the nonconstant ratio of these drugs in the plasma of the animal, the actual drug ratio to use for determining minimum inhibitory concentration (MIC) is unclear. Using the ratio of the total amount of each drug that is absorbed as a surrogate for the mean actual ratio may be the best alternative to current methods. Using this ratio as determined in these studies, (2.14:1 sulfadimethoxine:ormetoprim) to determine the MICs the single 50 mg/kg oral dose of the 5:1 combination of sulfadimethoxine and ormetoprim appears to provide plasma concentrations high enough to inhibit the growth of Yersinia ruckeri, Edwardsiella tarda, and Escherichia coli.

Disposition of sulfadimethoxine in male llamas (Llama glama) after single intravenous and oral administrations.

This study determined the disposition of sulfadimethoxine in six, healthy, adult, gelded male llamas (Llama glama) by using a nonrandomized crossover design with i.v. dosing (58.8 +/- 3.0 mg/kg based on metabolic scaling) followed by oral dosing (59.3 mg/kg +/- 8.3). Blood samples were collected intermittently for a 72-hr period, and serum sulfadimethoxine concentrations were quantified using high-performance liquid chromatography. Serum sulfadimethoxine concentrations across time were subjected to standard pharmacokinetic analysis based on linear regression. Mean maximum serum concentration after oral dosing was 23.6 +/- 14.9 microg/ml, and extrapolated peak concentration after i.v. administration was 246.6 +/- 15.8 microg/ml. Total clearance of sulfadimethoxine was 45.4 +/- 13.9 L/kg. Half-lives after i.v. and oral administration were 541 +/- 111 min and 642.4 +/- 204.8 min, respectively. Oral bioavailability was 52.6 +/- 15%. These data suggest that the oral dose administered to llamas in this study, based on metabolic scaling from cattle, may be inadequate when compared with the reported minimum inhibitory concentration (512 microg/ml) breakpoint for sulfadimethoxine.

Sulphonamide residues in eggs following drug administration via the drinking water.

The aim was to determine concentrations of sulphadimidine (SDM) and sulphadimethoxine (SDT) in eggs following oral administration through drinking water for 5 days (0.5 g l(-1) for SDT, 1 and 2 g l(-1) for SDM). Residues of sulphonamides in albumen and yolk were monitored by high-performance liquid chromatography with UV detection. The limit of quantification was 0.005 microg g(-1) for the two egg components. The results indicate that 0.9-1.4% of the dose administered was deposited in eggs. Maximum concentrations in albumen were much higher than those in yolk. More than 75% of the overall sulphonamides detected in eggs was concentrated in the albumen. The residue levels declined below the limit of quantification within 12-20 days for albumen and 14-15 days for yolk after treatment was discontinued.

Pharmacokinetics of sulfadimethoxine and sulfamethoxazole in combination with trimethoprim after oral single- and multiple-dose administration to healthy pigs.

The pharmacokinetics were studied of sulfadimethoxine (SDM) or sulfamethoxazole (SMX) in combination with trimethoprim (TMP) administered as a single oral dose (25 mg + 5 mg per kg body weight) to two groups of 6 healthy pigs. The elimination half-lives of SMX and TMP were quite similar (2-3 h); SDM had a relatively long half-life of 13 h. Both sulfonamides (S) were exclusively metabolized to N4-acetyl derivatives but to different extents. The main metabolic pathway for TMP was O-demethylation and subsequent conjugation. In addition, the plasma concentrations of these drugs and their main metabolites after medication with different in-feed concentrations were determined. The drug (S:TMP) concentrations in the feed were 250:50, 500:100, and 1000:200 mg per kg. Steady-state concentrations were achieved within 48 h of feed medication, twice daily (SDM+TMP) or three times a day (SMX+TMP). Protein binding of SDM and its metabolite was high (>93%), whereas SMX, TMP and their metabolites showed moderate binding (48-75%). Feed medication with 500 ppm sulfonamide combined with 100 ppm TMP provided minimum steady-state plasma concentrations (C(ss,min)) higher than the concentration required for inhibition of the growth of 90% of Actinobacillus pleuropneumoniae strains (n = 20).

Prevention of pleuropneumonia in pigs by in-feed medication with sulphadimethoxine and sulphamethoxazole in combination with trimethoprim.

The prophylactic effect of in-feed medication of conventional pigs with sulphadimethoxine (SDM), sulphamethoxazole (SMX), and trimethoprim (TMP) was tested by using an Actinobacillus pleuropneumoniae infection model. In each of five experiments, six pigs were given medicated feed twice daily and three pigs received antibiotic-free feed and served as positive (unmedicated, infected) controls. The following drugs or drug combinations were tested (in mg per kg feed): 500 SDM + 100 TMP, 500 SMX + 100 TMP, 125 SMX + 25 TMP, 125 SMX (alone) and 25 TMP (alone). After six days of feed medication, all animals were endobronchially inoculated with A. pleuropneumoniae in a dose of 1-3.10(4) colony-forming units (CFU). The response to the challenge in all control pigs was characterized by fever, lethargy, anorexia, reduced water consumption, and laboured breathing. At autopsy all controls manifested a fibrinous haemorrhagic pleuropneumonia. In-feed medication with 500 SDM + 100 TMP, 500 SMX + 100 TMP as well as 125 SMX + 25 TMP resulted in an effective protection against the challenge in all treated animals. After consumption of feed medicated with 125 mg per kg SMX or 25 mg per kg TMP, pleuropneumonia was evident in all challenged pigs. The results of this study indicate an in vivo potentiation of SMX and TMP in pigs against this respiratory tract pathogen.

Absorbability of sulphamonomethoxine and sulphadimethoxine administered via food of laying hens.

Sulphamonomethoxine (SMM) or sulphadimethoxine (SDM) were fed each to four laying hens at a dietary content of 400 p.p.m. 1000 p.p.m. of chromic oxide were supplemented to the experimental diets as an indicator for the absorbability in the gastrointestinal tract. SMM and SDM contents (p.p.m.) in the large intestine, determined 16 h after the start of feeding, were measured by HPLC. Average amounts of SMM and SDM in the dry matter of the large intestine were 12.3 and 30.2 p.p.m., respectively. The absorption ratios of SMM and SDM administered via the food were calculated to be 96.9 and 92.5%, respectively.

Comparison of ultrastructural changes in thyrotrophs of the rat pituitary between intermittent and continuous treatments with sulfadimethoxine.

To clarify relationships between serum thyroid-stimulating hormone (TSH) levels and ultrastructural changes in thyrotrophs caused by intermittent or continuous treatments with antithyroid compound, male Fischer-344 rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN) were given water containing 0.1% sulfadimethoxine (SM) for 8 wk and then sacrificed (Group 1). Additional groups were examined 2 wk after withdrawal (Group 2), after 4 wk retreatment following a 2-wk withdrawal period (Group 3), and after 14 wk continuous exposure (Group 4). Control rats (Group 5) remained untreated for 8 wk after the DHPN initiation. Microscopic examination revealed hypertrophy of thyrotrophs and depletion of TSH-positive material in Groups 1, 3, and 4 but a return to normal in Group 2. Electron microscopic examination of thyrotrophs in the anterior pituitary in Groups 1, 3, and 4 revealed dilated rough endoplasmic reticulum (ER) cisternae with intracisternal dense granules as well as diminished numbers of intracytoplasmic secretory granules, these changes being most marked in Group 1 and least pronounced in Group 4. The number of intracytoplasmic secretory granules in Group 3 was much lower than in Group 4, as demonstrated by morphometric analysis. In Group 2, thyrotrophs showed dilated rough ER cisternae without intracisternal dense granules and essentially the same component of intracytoplasmic secretory granules as Group 5. The present study suggest that while prolonged continuous treatment with SM results in gradual acclimation to an increased demand for TSH, intermittent treatment elicits a persistent state of reduced TSH storage in thyrotrophs due to a continued strong feedback through the hypothalamus-pituitary-thyroid axis.

Metabolism of 14C-sulphadimethoxane in swine.

1. 14C-sulphadimethoxine (4-amino-N-(2,6-dimethoxy-4-pyrimidinyl)benzene-[U-14C]-sulphonamide; 14C-SDM) was given orally (60 mg/kg body weight) to eight swine (weight 27-32 kg). Urine and faeces were collected from 0 to 72 h after dosing and tissue samples were collected from animals exsanguinated at 12, 24, 48 and 72 h after dosing. The concentration of total 14C-labelled residues (14C-SDM equivalents) in tissues other than the gastrointestinal tract ranged from 99-1 ppm (plasma) to 13.8 ppm (adipose tissue) 12 h after dosing. Seventy-two hours after dosing tissue concentrations ranged from 5.4 ppm (plasma) to 0.5 ppm (skeletal muscle). The concentration in the large intestine was substantially higher (10.4 ppm) than in the stomach (2.8 ppm) and small intestine (1.4 ppm) 72 h after dosing. 2. Of the 14C, 77% was excreted in the urine from 0 to 72 h after dosing with 14C-SDM, mostly in the 0-24-h collection. Fifteen percent was excreted in the faeces from 0 to 72 h after dosing, with most of this occurring 36-72 h post-dosing. 3. 14C-SDM accounted for 24% (liver) to 66% (adipose tissue) and the N4-acetyl derivative of SDM (N4-Ac-SDM) accounted for 10% (skeletal muscle) to 35% (kidney) of the total 14C in the tissues 12 h after dosing. The N4-glucose conjugate of SDM (G-SDM) was a major 14C-labelled compound in skeletal muscle (21% of total) and liver (28%) but it was not detected in adipose tissue or kidney. The N4-glucuronic acid conjugate of SDM (GA-SDM) was a minor metabolite in kidney, but was not detected in other tissues collected 12 h after dosing. Desamino SDM was a minor metabolite in the kidney. A minor metabolite in plasma was identified as the sulphate ester of 3-hydroxysulphadimethoxine. 4. 14C-labelled fractions isolated from 0 to 6-h urine included N4-Ac-SDM (82%), SDM (3%) and GA-SDM (6%).

[Demonstration of activity of two potentiated sulfonamides in feces of horses after oral or intravenous administration]. / Aktivitätsnachweis zweier potenzierter Sulfonamide in Kotproben von Pferden nach oraler oder intravenöser Verabreichung.

Both, the oral and intravenous application of two trimethoprim-potentiated sulfonamides induced measurable antibacterial activities in the feces of horses. With regard to the risk of antibiotic-induced alterations of the gastrointestinal flora, the route of application of potentiated sulfonamides seems to be of minor importance. The antibiotics used were Sulfadimethoxine/Trimethoprim (Trafigal 30% ad us. vet.) for oral and Sulfadoxine/Trimethoprim (Borgal 24% ad us. vet., both Hoechst AG, Frankfurt) for intravenous application. As recommended, both drugs were given in a dose of 20 mg per kg bodyweight. The detection method is based on a procedure layed down in German laws for sulfonamide residues in meat-samples and has undergone some modifications for the examination of feces.

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

Sulphamonomethoxine (SMM) or sulphadimethoxine (SDM) was fed to laying hens at 400 mg/kg diet for 5 successive days. After withdrawal of the drugs, contents (mg/kg) of SMM and SDM in the blood, kidney, liver, ovary, muscle and adipose tissue were determined by HPLC. 2. The disappearance of dietary SMM and SDM from the tissues of laying hens was rapid and, except for the liver, was very similar in all tissues. 3. A common biological half-life (t1/2) of SMM in the above 6 tissues was estimated to be 5.2 h. The t1/2 of SDM in the liver was 6.9 h, significantly longer than that of 4.4 h in the other 5 tissues. The values were much shorter than 51/2 (reported elsewhere) for other drugs. 4. Comparing the data found in this study with those obtained from previous papers, the depletion velocities of SMM and SDM from the hen's body were much faster than those from albumen in egg. The reason for this is probably related to the longer time period over which albumen formation occurs.

Absorption, tissue distribution, metabolism and excretion of ormetoprim and sulphadimethoxine in Atlantic salmon (Salmo salar) after intravenous and oral administration of Romet.

1. Uptake, bioavailability, tissue disposition and elimination of sulphadimethoxine (SDM) and ormetoprim (OMP) were examined in Atlantic salmon (Salmo salar) following intravenous and oral administration of Romet at a dose of 5 mg OMP and 25 mg SDM kg-1 fish. 2. Plasma clearance was rapid for both drugs following a single i.v. dose, characterized by t1/2 alpha = 0.48 and 0.54h, t1/2 beta = 9.9 and 25.6h for SDM and OMP respectively with a volume of distribution (Vss) = 0.389 and 2.478 l kg-1. 3. Following oral administration, peak plasma concentrations of 1.13 and 9.99 micrograms ml-1 were achieved after 17.6 and 20.3h for OMP and SDM respectively. Bioavailabilities were 85% for OMP and 39% for SDM. 4. Oral administration revealed the highest concentration of OMP in kidney and liver whereas the highest concentrations of SDM were found in muscle and bile. 5. High concentrations of N4-acetylated SDM were found in the bile indicating significant metabolism of SDM.

Pharmacokinetics of sulfadimethoxine and sulfamethoxazole in combination with trimethoprim after intravenous administration to healthy and pneumonic pigs.

The pharmacokinetics of two sulfonamide/trimethoprim combinations were investigated after intravenous administration to clinically healthy pigs and to the same pigs following a challenge with Actinobacillus pleuropneumoniae toxins. Endobronchial challenge with A. pleuropneumoniae toxins resulted in fever, increased white blood cell counts and decreased water and feed consumption. Healthy, as well as febrile, pigs were given sulfadimethoxine (SDM) or sulfamethoxazole (SMX) intravenously at a dose of 25 mg/kg b.w. in combination with 5 mg trimethoprim (TMP) per kg body weight. The pharmacokinetic parameters of the sulfonamides as well as their main metabolites (acetyl sulfonamides) were not significantly different in healthy and febrile pigs. In healthy and pneumonic pigs, the mean elimination half-lives of SDM were 12.9 h and 13.4 h, respectively, those of SMX 2.5 h and 2.7 h, respectively, and those of TMP 2.8 h and 2.6 h, respectively. Distribution volumes in healthy and febrile pigs of SDM and SMX varied between 0.2 and 0.4 L/kg, and those of TMP between 1.1 and 1.6 L/kg. The mean AUC of TMP was decreased and the volume of distribution and total body clearance of TMP were increased in febrile pigs. Protein binding of the drugs and metabolites studied were not significantly changed after toxin-induced fever. The extent of protein binding of SDM, SMX and TMP was in the range 94-99%, 45-56% and 40-50%, respectively. Based on knowledge of in vitro antimicrobial activity of the drug combinations against A. pleuropneumoniae it was concluded that after intravenous administration of the dose administered (30 mg/kg of the combination preparations) to healthy and pneumonic pigs, plasma concentrations of SMX and TMP were above the concentration required for growth inhibition of 50% of A., pleuropneumoniae strains for approximately 16 h, whereas bacteriostatic plasma concentrations of SDM were still present after TMP had been eliminated from plasma. Because of similar elimination half-lives of SMX and TMP in pigs this combination is preferred to the combination of SDM with TMP.