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A comprehensive ecotoxicological evaluation of a sulfamethazine (SMZ) and sulfamethoxazole (SMX) mixture was conducted using an indicator microalga, Scenedesmus obliquus. The toxicological effects of this mixture were studied using microalgal growth patterns, biochemical characteristics (total chlorophyll, carotenoid, carbohydrate, fatty acid methyl ester), and elemental and Fourier-transform infrared spectroscopy analyses. The 96-h half maximal effective concentration (EC 50 ) of the SMZ and SMX mixture was calculated to be 0.15 mg L -1 according to the dose-response curves obtained. The chlorophyll content decreased with elevated SMZ and SMX concentrations, while the carotenoid content initially increased and then decreased as concentration raised. The unsaturated fatty acid methyl esters (FAMEs) content was enhanced with higher SMZ and SMX concentrations, while that of saturated FAMEs simultaneously decreased due to SMZ and SMX stress. Elemental analyses showed an improved percentage of nitrogen and sulfur in the microalgal biomass as SMZ and SMX concentrations increased. The microalga S. obliquus was shown to biodegrade the chemicals tested and removed 31.4-62.3% of the 0.025-0.25 mg SMZ L -1 and 27.7-46.8% of the 0.025-0.25 mg SMX L -1 in the mixture after 12 days of cultivation. The greater biodegradation observed at higher SMZ and SMX concentrations indicates that microalgal degradation of SMZ and SMX could act as an efficient adaptive mechanism to antibiotics., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Engineering of pharmaceutical cocrystals is an advantageous alternative to salt formation for improving the aqueous solubility of hydrophobic drugs. Although, spray drying is a well-established scale-up technique in the production of cocrystals, several issues can arise such as sublimation or stickiness due to low glass transition temperatures of some organic molecules, making the process very challenging. Even though, fluidised bed spray coating has been successfully employed in the production of amorphous drug-coated particles, to the best of our knowledge, it has never been employed in the production of cocrystals. The feasibility of this technique was proven using three model cocrystals: sulfadimidine (SDM)/4-aminosalicylic acid (4ASA), sulfadimidine/nicotinic acid (NA) and ibuprofen (IBU)/ nicotinamide (NAM). Design of experiments were performed to understand the critical formulation and process parameters that determine the formation of either cocrystal or coamorphous systems for SDM/4ASA. The amount and type of binder played a key role in the overall solid state and in vitro performance characteristics of the cocrystals. The optimal balance between high loading efficiencies and high degree of crystallinity was achieved only when a binder: cocrystal weight ratio of 5:95 or 10:90 was used. The cocrystal coated beads showed an improved in vitro-in vivo performance characterised by: (i) no tendency to aggregate in aqueous media compared to spray dried formulations, (ii) enhanced in vitro activity (1.8-fold greater) against S. aureus, (iii) larger oral absorption and bioavailability (2.2-fold higher C max ), (iv) greater flow properties and (v) improved chemical stability than cocrystals produced by other methods derived from the morphology and solid nature of the starter cores., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Successful delivery of a DNA vaccine to antigen-presenting cells and their subsequent stimulation of CD4 + and CD8 + T cell immunity remains an inefficient process. In general, the delivery of prophylactic vaccines is mainly mired by low transfection efficacy, poor immunogenicity, and safety issues from the materials employed. Currently, several strategies have been exploited to improve immunogenicity, but an effective strategy for safe and pain-free delivery of DNA vaccines is complicated. Herein, we report the rapid delivery of polyplex-based DNA vaccines using microneedle arrays coated with a polyelectrolyte multilayer assembly of charge reversal pH-responsive copolymer and heparin. The charge reversal pH-responsive copolymer, composed of oligo(sulfamethazine)-b-poly(ethylene glycol)-b-poly(amino urethane) (OSM-b-PEG-b-PAEU), was used as a triggering layer in the polyelectrolyte multilayer assembly on microneedles. Charge reversal characteristics of this copolymer, that is, the OSM-b-PEG-b-PAEU copolymer exhibit, positive charge at low pH (pH4.03) and becoming negative charge when exposed to physiological pH conditions (pH7.4), allowing the facile assembly and disassembly of polyelectrolyte multilayers. The electrostatic repulsion between heparin and OSM-b-PEG-b-PAEU charge reversal copolymer triggered the release of DNA vaccines. DNA vaccines laden on microneedles are effectively transfected into RAW 264.7 macrophage cells in vitro. Vaccination of BALB/c mice by DNA vaccine-loaded microneedle arrays coated with a polyelectrolyte multilayer generated antigen-specific robust immune responses. These findings provide potential strategy of charge reversal pH-responsive copolymers coated microneedles for DNA vaccine delivery., (Copyright © 2017. Published by Elsevier B.V.)

Sulfamethazine (SMZ) is one of the most commonly used sulfonamide compounds in fish farming, and its physiological effects on fish are unknown. SMZ was administered to juvenile Nile tilapia (Oreochromis niloticus) at a dose level of 422 mg kg(-1) body weight, for a period of 11 days, via medicated feed. Fish were divided into two groups, the control group (CG) and the group fed with SMZ in feed. The administration of SMZ did not alter the erythrograms and leukograms of the Nile tilapia. The SMZ-fed group showed the same hepatic lipid peroxidation (LPO) concentration as the CG. Nonetheless, the oral administration of SMZ raised the hepatic catalase (CAT) and glutathione S-transferase (GST) activities, the increase probably being sufficient to prevent hepatic LPO production. The oral administration of SMZ affects the hepatic GST and CAT activities of Nile tilapia.

The oral pharmacokinetics of three sulfonamides, sulfadimidine (pKa 7.5), sulfadiazine (pKa 6.5) and sulfanilamide (pKa 10.5), with different rates of unionization in rumen juice, were compared in Shiba goats to clarify the relationship between drug absorption profiles after their oral administration as well as their degree of unionization in the rumen. Sulfonamides were administered either into the left jugular vein or orally to five male goats at doses of 10 mg/kg body weight, using a crossover design with at least a 3-week washout period. The Tmax of sulfadimidine, sulfadiazine and sulfanilamide reached 2.0 ± 1.2, 6.0 ± 0.0, and 7.8 ± 1.6 hr, respectively, after their oral administration, and this was followed by their slow elimination due to a slow rate of drug absorption from the gastrointestinal tract. The MAT and t1/2ka of sulfadiazine (13.2 ± 2.0 and 10.9 ± 1.08 hr) were significantly longer than those of sulfanilamide (9.09 ± 1.67 and 7.46 ± 1.70 hr) and sulfadimidine (7.52 ± 0.85 and 5.17 ± 0.66 hr). These results suggest that the absorption rates of highly unionized drugs (such as sulfanilamide and sulfadimidine) from the forestomach of goats may be markedly higher than less unionized ones (such as sulfadiazine). The mean oral bioavailability of sulfadiazine was high (83.9 ± 17.0%), whereas those of sulfadimidine and sulfanilamide were low (44.9 ± 16.4% and 49.2 ± 2.11%, respectively).

Coccidiosis is a protozoal and occasionally fatal diarrheic disease of goats imposing heavy economic losses to farming community. This study aimed to evaluate the efficacies of Furazolidone, Sulfadimidine and Amprolium against coccidiosis in Beetal goats. Twenty-four (24) Beetal goats naturally infected with coccidiosis were randomly divided into four groups of 6 (A-D). Goats in groups A, B and C were treated orally with Furazolidone (10 mg/Kg), Sulfadimidine (100 mg/Kg) and Amprolium (55 mg/Kg), respectively for 7 days. Goats in-group D served as positive control. Oocysts per gram (OPG) of feces counts of individual goats in each group were performed on Days; 0 (pre-treatment) 7, 14 and 21 (post-treatment). OPG counts amongst goats in all groups at day 0 were not significant (P>0.05). On days 7, 14 and 21, OPG values decreased significantly (P<0.05) in groups A, B and C compared to group D. The efficacy of Furazolidone, Sulfadimidine and Amprolium was 98.6, 98.0 and 99.6 percent, respectively on Day 21 (end of trial). Statistically, the efficacies of three drugs were not significantly different (P>0.05). In conclusion, Furazolidone, Sulfadimidine and Amprolium are well-tolerated and any one of these may be recommended to effectively treat coccidiosis in Beetal goats.

Objective: To monitor concentrations of sulfadimidine in the paranasal sinus mucosa (PSM) of unsedated horses following IV administration of trimethoprim-sulfadimidine via in vivo microdialysis., Animals: 10 healthy adult horses., Procedures: Concentric microdialysis probes were implanted into the subepithelial layers of the frontal sinus mucosa of standing sedated horses. Four hours after implantation, trimethoprim-sulfadimidine (30 mg/kg) was administered IV every 24 hours for 2 days; dialysate and plasma samples were collected at intervals during that 48-hour period and analyzed for concentrations of sulfadimidine. The dialysate concentration and relative loss of sulfadimidine from the perfusate were used to calculate the PSM concentration., Results: Microdialysis probe implantation and subsequent in vivo microdialysis were successfully performed for all 10 horses. Following the first and second administration of trimethoprim-sulfadimidine, mean ± SD peak concentrations of sulfadimidine were 55.3 ± 10.3 μg/mL and 51.5 ± 8.7 μg/mL, respectively, in plasma and 9.6 ± 4.5 μg/mL and 7.0 ± 3.3 μg/mL, respectively, in the PSM. Peak sulfadimidine concentrations in the PSM were detected at 5.9 ± 2.7 hours and 5.4 ± 2.3 hours following the first and second drug administrations, respectively. For 12 hours, mean PSM sulfadimidine concentration remained greater than the minimum inhibitory concentration indicative of sulfonamide susceptibility of equine bacterial isolates (4.75 μg/mL)., Conclusions and Clinical Relevance: In vivo microdialysis for continuous monitoring of PSM sulfadimidine concentrations in unsedated horses was feasible. Intravenous administration of trimethoprim (5 mg/kg) and sulfadimidine (25 mg/kg) proved likely to be efficient for treating sinusitis caused by highly susceptible pathogens, providing that the dosing interval is 12 hours.

The use of water medications is a common practice in the US swine industry to treat and prevent infections in swine herds with minimal labor and without risk of needle breakage. There are concerns that FDA-approved withdrawal times (WDT) may be inadequate for several water medications when exporting pork products to countries where MRLs (maximum residue limits) are lower than US tolerance levels. In this study, withdrawal intervals (WDI) were estimated for pigs when dosed with tetracycline and sulfamethazine in water. The WDI were calculated using the FDA tolerance method (TLM) and a population-based pharmacokinetic method (PopPK). The estimated WDIs (14-16 days using TLM) were similar to the approved WDT of 15 days for sulfamethazine. However, the PopPK method extended WDIs for both sulfamethazine (19-20 days) and tetracycline (12 days) compared to the currently approved WDTs in the U.S. This study also identified potential differences in WDI between weanling and finisher pigs. In conclusion, the TLM may not always provide adequate WDT for foreign export markets especially when MRLs differ from tolerance levels approved for US markets. However, PopPK methods can provide conservative WDIs in situations with considerable variability in medication exposure such as with administration in water., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Escherichia coli strains isolated from fecal samples were screened to examine changes in phenotypic and genotypic characteristics including antimicrobial susceptibility, clonal type, and carriage of resistance determinants. The goal of this 197-day study was to investigate the influence of administration of chlortetracycline alone (T) or in combination with sulfamethazine (TS) on the development of resistance, dissemination of defined strain types, and prevalence of resistance determinants in feedlot cattle. Inherent tetracycline resistance was detected in cattle with no prior antimicrobial exposure. Antimicrobial administration was not found to be essential for the maintenance of inherently ampicillin-resistant and tetracycline-resistant (Tet(r)) E. coli in control animals; however, higher Tet(r) E. coli shedding was observed in animals subjected to the two treatments. At day 0, high tetracycline (26.7%), lower sulfamethoxazole-tetracycline (19.2%), and several other resistances were detected, which by the finishing phase (day 197) were restricted to ampicillin-tetracycline (47.5%), tetracycline (31.7%), and ampicillin-tetracycline-sulfamethoxazole (20.8%) from both treated and untreated cattle. Among the determinants, bla(TEM1), tet(A), and sul2 were prevalent at days 0 and 197. Further, E. coli from day 0 showed diverse antibiogram profiles and strain types, which by the finishing phase were limited to up to three, irrespective of the treatment. Some genetically identical strains expressed different phenotypes and harbored diverse determinants, indicating that mobile genetic elements contribute to resistance dissemination. This was supported by an increased linked inheritance of ampicillin and tetracycline resistance genes and prevalence of specific strains at day 197. Animals in the cohort shed increasingly similar genotypes by the finishing phase due to animal-to-animal strain transmission. Thus, characterizing inherent resistance and propagation of cohort-specific strains is crucial for determining antimicrobial resistance in cattle.

Sulphonamides are still being used widely, influenced by the low cost and the efficacy against many common bacterial infections, since they present a broad spectrum of activity. The aim of this study was to determine the effect of age on the pharmacokinetic/pharmacodynamics (PK/PD) integration of intravenous sulfamethazine (60 mg/kgbw) in cattle, and the possible therapeutic outcomes. Six healthy female calves, at the age of one, three, seven and fifteen weeks were used. Normality analysis was assessed with the Shapiro-Wilk test. Non-parametric tests for paired data were used. Plasma concentrations were quantified using HPLC/uv. Differences were found between one-three-weeks-old calves and seven-fifteen-weeks-old calves, in pharmacokinetic parameters (clearance, area under the concentration-time curve and elimination half-life) and in the PK/PD integration. The ratios obtained in PK/PD integration (T>MIC, WAUC) confirm that it is necessary to apply twice the dose of sulfamethazine in > or = 7 weeks-old cattle to reach a satisfactory dosage regimen (MIC > or = 32 microg/mL).

Neurons located in the lateral septal organ (LSO) and medial basal hypothalamus (MBH) have been proposed to be encephalic photoreceptors (EPRs), which sense photoperiodic time and initiate avian gonadal development. Controversy continues regarding the location of EPRs serving the PNES and their signal transduction pathway. Using quantitative real-time RT-PCR we determined activation of key genes following prolonged light periods and sulfamethethazine (compound known to advance light-induced testes development) in 21-day old chicks. Earliest activation occurred in genes of vasoactive intestinal polypeptide (VIP) and type 6 phosphodiesterase beta subunit (PDE-6 beta) in the LSO at 4 and 6h, respectively, after onset of light and sulfamethazine intake. In contrast, no change was detected in the MBH during the first 8h of that treatment. Thereafter, significant increases in gonadotropin releasing hormone (GnRH-1) and VIP receptor (VIPR) mRNA transcripts were detected in the bed nucleus of the pallial commissure (NCPa). Hours later, activation of all four genes (VIP, PDE-6 beta, GnRH-1, VIPR) were induced solely by photostimulation. Deiodinase 2 and tyrosine hydroxylase in the MBH did not show increased gene expression until 12h of photostimulation. Prolactin mRNA transcripts showed significant increases at 4h due to SMZ intake and at 24, 36 and 48 h due to long-day photoperiodic effects. Data suggest that VIP neurons in the LSO may serve as EPRs and utilize PDE, present in the phototransduction cascade of known photoreceptors. Additionally, VIP released from the LSO may modulate GnRH-1 neurons in the NCPa via VIP receptors by increasing GnRH-1 gene expression.

Sulfamethazine is often used to treat disease in the swine industry. Sulfamethazine is available as water or feed medication and historically (over the past 40 years) has been associated with residue violations in both the United States and Europe. Despite sulfamethazine's approval for use as a water medication, little research on the pharmacokinetics of the water formulation is available. Therefore, a pilot study was performed to determine the plasma levels of an approved sulfamethazine water medication. Plasma levels in pigs treated with an oral bolus (250 mg/kg), which is equivalent to the total drug consumed within a 24-h period, achieved therapeutic concentrations (50 microg/ml). Noncompartmental-based pharmacokinetic model parameters for clearance, half-life, and volume of distribution were consistent with previously published values in swine. However, the above treatment resulted in exposure of pen mates to sulfamethazine at levels currently above tolerance (0.1 ppm). Using a physiologically based pharmacokinetic model, the treatment dose simulation was compared with observed plasma levels of treated pigs. Flexibility of the physiologically based pharmacokinetic model also allowed simulation of control-pig plasma levels to estimate contamination exposure. A simulated exposure to 0.15 mg/kg twice within approximately 8 h resulted in detectable levels of sulfamethazine in the control pigs. After initial exposure, a much lower dose of 0.059 mg/kg maintained the contamination levels above tolerance for at least 3 days. These results are of concern for producers and veterinarians, because in commercial farms, the entire barn is often treated,and environmental contamination could result in residues of an unknown duration.

Low level intake of drugs from the ingestion of contaminated feed may lead to residue problems in food animals. Sulfadimidine (SDD) was used as a model to determine the residue risk at various doses in laying hens. The drug was administered as a single intravenous injection (100 mg kg(-1) body weight, BW), as a single oral dose (100, 30, 10, 3, 1 mg kg(-1) BW) and via medicated feed for 7 consecutive days (30, 10, 3 mg kg(-1) BW). Drug levels were determined with HPLC-UV for plasma, yolk and albumen. Pharmacokinetic values, which were calculated using a first-order one-compartment model, residue levels and transfer rates into the eggs were found to be dose-dependent. Even low doses of 3 and 1 mg kg(-1) BW resulted in measurable residues in yolk and albumen 1 day after a single oral administration. After ingestion of medicated feed at 3 mg kg(-1) BW, mean drug levels at 0.14 +/- 0.01 microg g(-1) were found in albumen and at 0.09 +/- 0.01 microg ml(-1) in plasma. Generally, the residue levels in albumen and plasma were higher than in yolk. These findings demonstrate a residue risk for the consumer even after low level intake of drugs.

The bolus (or oblet) is a dosage form that can be used for the oral administration of pharmaceutical compounds to ruminating species. Unlike traditional tablets, oral boluses may contain quantities of drug on the order of grams rather than milligrams. Due to its size, it is only recently that USP-like in vitro dissolution methods have been developed for this dosage form. However, whether or not these dissolution tests can predict product in vivo performance has yet to be determined. The importance of this issue is apparent when the U.S. Food and Drug Administration Center for Veterinary Medicine is faced with the decision of whether to require additional in vivo bioequivalence study data to support the approval of changes in product chemistry or manufacturing method. The current study was undertaken to determine whether an in vivo/in vitro correlation can be established for bovine sulfamethazine oral boluses and to acquire insight into the magnitude of changes in in vitro product performance that can occur before corresponding changes are seen in in vivo blood level profiles. Based upon the results of this investigation, it is concluded that marked changes in in vitro sulfamethazine bolus performance can be tolerated before resulting in altered in vivo blood level profiles. However, the data also suggest that rumenal absorption may occur for some compounds. Therefore the degree to which variation in product in vitro dissolution profiles can be tolerated may be compound specific.

The presence of antimicrobial agents in edible tissues of food-producing animals remains a major public health concern. Probabilistic modeling techniques incorporated into a physiologically based pharmacokinetic (PBPK) model were used to predict the amounts of sulfamethazine residues in edible tissues in swine. A PBPK model for sulfamethazine in swine was adapted to include an oral dosing route. The distributions for sensitive parameters were determined and were used in a Monte Carlo analysis to predict tissue residue times. Validation of the distributions was done by comparison of the results of a Monte Carlo analysis to those obtained with an external data set from the literature and an in vivo pilot study. The model was used to predict the upper limit of the 95% confidence interval of the 99th percentile of the population, as recommended by the U.S. Food and Drug Administration (FDA). The external data set was used to calculate the withdrawal time by using the tolerance limit algorithm designed by FDA. The withdrawal times obtained by both methods were compared to the labeled withdrawal time for the same dose. The Monte Carlo method predicted a withdrawal time of 21 days, based on the amounts of residues in the kidneys. The tolerance limit method applied to the time-limited data set predicted a withdrawal time of 12 days. The existing FDA label withdrawal time is 15 days. PBPK models can incorporate probabilistic modeling techniques that make them useful for prediction of tissue residue times. These models can be used to calculate the parameters required by FDA and explore those conditions where the established withdrawal time may not be sufficient.

Here we identify, using nonelectrophoretic proteomics, effects of subminimum inhibitory concentrations (subMIC) of two antibiotic preparations, chlortetracycline (CTC), and chlortetracycline-sulfamethazine (CTC + SMZ), on protein expression in the bovine respiratory pathogen Mannheimia haemolytica. The M. haemolytica genome is currently in draft form, and annotation is incomplete. Relying on the principle of gene sequence conservation across species, we used annotated genomes from closely related species to identify, confirm, and functionally annotate 495 M. haemolytica proteins. To conduct quantitative comparative proteomics, we developed a protein quantitation method based on the cross correlation function of the SEQUEST algorithm. When M. haemolytica was cultivated in the presence of 1/4 MIC of CTC and CTC + SMZ, expression of proteins involved in energy production, nucleotide metabolism, translation, and the bacterial stress response (chaperones) were affected. The most notable subMIC effect was a significant decrease in the expression of leukotoxin A, which is an important M. haemolytica virulence factor. Reduction in leukotoxin expression could be one of the molecular mechanisms responsible for the efficacy of these antibiotics against bovine respiratory disease.

Objective: To develop a flow-limited, physiologic-based pharmacokinetic model for use in estimating concentrations of sulfamethazine after IV administration to swine., Sample Population: 4 published studies provided physiologic values for organ weights, blood flows, clearance, and tissue-to-blood partition coefficients, and 3 published studies provided data on plasma and other tissue compartments for model validation., Procedure: For the parent compound, the model included compartments for blood, adipose, muscle, liver, and kidney tissue with an extra compartment representing the remaining carcass. Compartments for the N-acetyl metabolite included the liver and the remaining body. The model was created and optimized by use of computer software. Sensitivity analysis was completed to evaluate the importance of each constant on the whole model. The model was validated and used to estimate a withhold interval after an IV injection at a dose of 50 mg/kg. The withhold interval was compared to the interval estimated by the Food Animal Residue Avoidance Databank (FARAD)., Results: Specific tissue correlations for plasma, adipose, muscle, kidney, and liver tissue compartments were 0.93, 0.86, 0.99, 0.94, and 0.98, respectively. The model typically overpredicted concentrations at early time points but had excellent accuracy at later time points. The withhold interval estimated by use of the model was 120 hours, compared with 100 hours estimated by FARAD., Conclusions and Clinical Relevance: Use of this model enabled accurate prediction of sulfamethazine pharmacokinetics in swine and has applications for food safety and prediction of drug residues in edible tissues.

A steady-state bioconcentration and elimination of sulfamethazine (SM(2)) in the sturgeon (A. schrenkii) was conducted in flow-through aqueous conditions. Two treated groups of fish were exposed to concentrations of 1.00 and 0.10 mg/L of SM(2), respectively. SM(2) and its main metabolite, N(4)-acetyl-SM(2), were determined in both fish muscle and water during the 8-day uptake period and the subsequent 6-day elimination period. Rapid uptakes of the drug were observed in both treated groups. Muscle tissue residues plateaued after approximately 3 days. The bioconcentration factor in muscle (BCF(m)) in the low-concentration drug solution was 1.19 and that in the high-concentration-treated level was 0.61. The calculated biodegradation index was 3.72%. The elimination half-times (t(1/2)) of the two treatment levels were 19.44 and 23.52 h, respectively. The result indicates that SM(2) will neither bioconcentrate in individual aquatic organisms nor biomagnify in the food chain, although the BCF(m) was relatively higher under the low-concentration exposure.

Comparative, in vivo, human, prospective, single blind, clinical and microbiological diagnoses based and randomised study of the treatment of uncomplicated bacterial vaginosis with two forms of combined (metronidazole + nystatin + sulfadimidin) vaginal suppositories (laminated and mixed containing the same ingredients) and the standard preparations available in the Hungarian market (Dalacin vaginal cream and Klion vaginal suppository). The examinations involved 60 volunteers and were performed in the Gynecological Outpatient Clinic of the Council of Erd, the microbiological samples were examined at Saint Rókus Hospital in Budapest. The combined treatment was better tolerated and resulted in normal vaginal pH significantly more often at the same rate of recovery. The combined treatment is simultaneously effective in cases of the most prevalent coinfections too.

The authors elaborated noninvasive method to diagnose acetylation phenotype through photocolorimetric studying kinetics of sulfadimesine urinary excretion. Suggestion is approach to people protection through selection of inductors which purposefully increase individual activity of N-acetyltransferase.

The distribution of total 14C residues was studied in egg yolk and albumen after administration of either single or multiple oral dosages of [14C]sulfamethazine (SMZ). One day after a single dose of [14C]SMZ (121 mg of sulfamethazine, 2.42 x 10(7) dpm), the 14C residue concentration peaked in egg albumen and egg yolk with the concentration in the former >4-fold greater than in the latter. Three days postdose, the 14C residue concentration in the yolk was approximately 7-fold higher than in the egg albumen. A multiple dose of [14C]SMZ containing sulfamethazine mass equivalent of an average therapeutic dose (282 mg, 2.9 x 10(7) dpm) for chickens was also administered orally for six consecutive days to hens. A significantly reduced level of egg production was observed during the medication, and most of the hens stopped laying eggs after the last dose. The 14C residue concentrations peaked on the last day (sixth) of medication in egg albumen and yolk. The 14C residue concentrations were also measured in liver, muscle, blood, and plasma of chickens sacrificed at 1, 24, 48, and 72 h after the last dose. Highest concentrations of 14C residue were accumulated in liver followed by, in decreasing order, blood, plasma, and muscle.

Pharmacokinetics and urinary excretion of sulphadimidine (SDI) were determined in buffalo calves following single oral administration (150 mg/kg). The plasma levels of free sulphadimidine were above minimum effective therapeutic concentration (> 40 micrograms/ml) between 4 and 12 h and the N4-acetylated form of the drug was in the range of 7.2-19.3%. Kinetic evaluation of plasma levels was performed using a two-compartment open model. The absorption and elimination half-lives of SDI were 3.01 and 11.94 h, respectively. Based on this study, an optimal dosage regimen of sulphadimidine in buffalo calves would be 100 mg/kg, followed by 50 mg/kg at 12 h intervals. Sulphadimidine was mainly excreted in the urine as free amine. The percentage of N4-acetyl sulphadimidine in urine was comparatively higher than in plasma.

Thirty-eight, one- to two-week-old calves with experimentally induced Escherichia coli diarrhoea were randomly assigned to three treatment groups. Two groups of 15 calves were treated intramuscularly once daily for three days with either danofloxacin mesylate at 1.25 mg/kg bodyweight, or with baquiloprim/sulphadimidine as a positive control (10 mg of combined active ingredient/kg); eight calves were treated with 0.9 per cent sodium chloride solution as a negative control (1 ml/20 kg). Faecal consistency, demeanour, hydration status, appetite and bodyweight were monitored before, during, and for four days after treatment by an investigator unaware of the animals' treatment. Before treatment, the clinical, biochemical, and faecal indices were similar among the groups. By 24 hours after treatment began, the proportion of observations of faeces recorded as of normal consistency was highest in the danofloxacin-treated group (26 of 60), compared with 16 of 60 in the baquiloprim/sulphadimidine treated groups and four of 32 in the control group. The proportion of calves with a normal demeanour was highest in the danofloxacin-treated group at all the evaluations and these calves gained significantly (P < 0.05) more weight (1.6 [0.27] kg) than the calves treated with baquiloprim/sulphadimidine (0.67 [0.36] kg). The calves in the danofloxacin-treated group maintained relatively normal blood pH values, whereas the calves in the control group became progressively acidotic. By the end of treatment, the mean bicarbonate concentration was significantly (P < 0.05) higher in the danofloxacin-treated calves than in the control group. The pH of the calves in the baquiloprim/sulphadimidine-treated group changed little during treatment, but by three days after the last treatment their mean pH had dropped to the level of the calves in the control group. The mean bicarbonate concentration of the baquiloprim/sulphadimidine-treated calves, like that of the danofloxacin-treated calves, was significantly (P < 0.05) higher than that of the calves in the control group.

Salivary output in sheep is large enough to be considered a physiologic body fluid compartment. The hypothesis for this work was that pharmacokinetics of sulfamethazine in saliva was similar to that in plasma. A reliable technique was developed to measure parotid salivary output. Mean output of saliva was 3.18 +/- 1.04 L from a single parotid gland per day with a mean flow of 2.21 +/- 0.43 mL/min. Using concentrations of sulfamethazine in parotid saliva made it possible to calculate the total passage of sulfamethazine to parotid saliva, which was calculated to be 3.5% of the total dose. Pharmacokinetic variables obtained for sulfamethazine in plasma and in saliva were closely related (AUC 1408 micrograms.h/mL and AUC 1484 micrograms.h/mL; Vdarea 0.434 L/kg and Vdarea 0.374 L/kg; t 1/2 beta 4.30 h and 3.46 h, respectively) and no substantial differences were observed. The convenience of using salivary concentrations of sulfamethazine for drug monitoring is discussed.

Twelve calves aged 6-10 months, and 12 calves aged 10-16 months were turned out onto a permanent pasture known to have been contaminated with oocysts of Eimeria alabamensis during the previous year. Two days after turnout, six of the older calves and six of the younger were each treated with one bolus per 200 kg bodyweight containing 1.6 g baquiloprim and 14.4 g sulphadimidine. The other 12 calves were left untreated. The excretion of Eimeria oocysts, the faecal dry matter and the weight gain of treated and untreated calves within each age group were compared during the first 3 weeks on pasture to assess the efficacy of the bolus in preventing E. alabamensis coccidiosis. All the older of the untreated calves and four of the younger developed gruel-like to watery diarrhoea 4-7 days after turnout. The faecal consistency of the treated calves remained firm and they lost significantly less weight than the control calves during the first 13 days on pasture. The treated calves also excreted significantly fewer oocysts during the first 20 days of grazing; their oocyst excretion remained low during days 8-10 when all but one of the diarrhoeic control calves excreted more than 850,000 oocysts per gram faeces (OPG). Starting on days 12 to 14 the oocyst excretion of 8 of the treated calves increased to 20,000-65,000 OPG and of 2 calves to 210,000-240,000 OPG. There was no difference in oocyst output between treated and untreated calves from the fourth week of grazing and no difference in weight gain among the younger calves. In the older calves there was a tendency for the untreated calves to gain more weight than treated calves.

The effect of water deprivation on the pharmacokinetic parameters of antipyrine and sulphadimidine in the Nubian goat was studied. Water deprivation, to a level of dehydration at which the animals lost an average of 7.5% body weight, resulted in a significant reduction in antipyrine clearance (p < 0.05), and a consequently increased AUC value (p < 0.05). No effect was observed on the distribution parameters of the drug. In dehydrated animals which had lost an average of 10% or 12.5% of their body weight owing to water deprivation, significant changes were found in the distribution and elimination pharmacokinetic parameters of antipyrine and sulphadimidine. The volume of distribution was significantly decreased, resulting in elevated plasma levels for the two drugs compared to normally watered animals. Significant decreases in clearance and subsequent prolongation of the elimination half-lives were observed during these periods of water deprivation. These changes in the disposition kinetics of the two drugs may be attributed to the loss of total body water and extracellular fluids and changes in the liver and kidney functions taking place during dehydration.

Twenty-three hybrid pigs (23 +/- 3 kg body wt) were assigned to three groups to investigate the pharmacokinetics of ampicillin (APC, 10 mg/kg) administered intravenously (i.v.) and intramuscularly (i.m.), and sulfadimidine (SDM, 50 mg/kg) administered intravenously as a bolus injection. In the first series of experiments the animals remained healthy. Subsequently, the pigs were infected with Streptococcus suum by subcutaneous (s.c.) inoculation and the experiments were repeated. The total apparent distribution volume of APC given intravenously was increased from 0.512 +/- 0.026 L/kg in uninfected pigs to 0.68 +/- 0.06 L/kg (P < 0.01) in infected pigs, whereas there were no significant changes in the same parameter for SDM (P > 0.05). The clearance of APC was increased markedly from 0.52 +/- 0.07 L/kg/h in uninfected pigs to 0.62 +/- 0.10 L/kg/h in infected pigs. In contrast, SDM clearance was decreased markedly from 0.023 +/- 0.003 L/kg/h to 0.017 +/- 0.003 L/kg/h (P < 0.05). As a result, the biological half-lives of the drugs were altered to varying degrees in infected pigs. The half-life of SDM was increased from 15.0 +/- 3.0 h in uninfected pigs to 20 +/- 7h in infected pigs (P < 0.05), but differences in APC half-lives between uninfected and infected animals were not observed (P > 0.05). There were no statistically significant differences in pharmacokinetic parameters of APC administered by intramuscular injection between the healthy and the diseased status, although its half-life was shortened from 0.76 +/- 0.22 h in the healthy to 0.57 +/- 0.23 h in the diseased. The results suggest that blood concentrations of APC and SDM are affected differently by the same disease due to its specific effects on their distribution and elimination.

Sulfamethazine (SMZ) administration (ip, 3 d) of different doses to adult male rats showed significant increases in the electron transport components and activities of aminopyrine N-demethylase and aniline hydroxylase at the the 150 mg SMZ/kg dose level. However, 300 mg SMZ/kg doses produced a significant decrease in cytochrome P-450 and the activity of aminopyrine N-demethylase. In a longer duration study, 300 mg SMZ/kg caused significant decreases in cytochrome P-450 and in the activity of aminopyrine N-demethylase. The inducer dose of 150 mg SMZ/kg and the inhibitory dose of 300 mg SMZ/kg were selected for dosing young male, old male and adult female rats. Sulfamethazine administration to young male rats resulted in a significant induction of electron transport components and drug metabolizing enzymes at both dose levels. However, SMZ treatment of old rats produced significant decreases in electron transport components and aminopryine N-demethylase activity at both dose levels. A significant induction in the levels of electron transport components was observed with 150 mg SMZ/kg in female rats. All other parameters were unchanged. Sulfamethazine resulted in a mixed type of inhibition (Ki = 3.5 mM) of aminopyrine N-demethylase in vitro. Hydroxylated metabolites destructed the spectral and catalytic activity of cytochrome P-450. Our studies suggest that SMZ is a substrate of the mixed function oxidase system and induction is dependent on dosage, age and sex of the animals.

The bioavailability of two different forms of medicated feed containing 2000 mg sulfadimidine (SDM) per kg was determined in three groups of eight piglets. In the first group, pharmacokinetic parameters of SDM were determined after a single intravenous dose of 10 mg/kg body weight and after single oral doses of 45 mg/kg body weight ingested either as an oleus solution sprayed directly onto the feed pellets ready for use (SPR) or as a commercially available premix incorporated into the feed before pelletising (PMX). After the single intravenous administration, the mean +/- SD of the volume of distribution was 0.34 +/- 0.05 l/kg, the total body clearance 0.37 +/- 0.07 ml/min.kg, the mean residence time 15.5 +/- 2.5 h, and the elimination half-life 11.1 +/- 2.0 h. Although no statistical significance existed, a single meal with PMX was associated with slightly higher mean values for the maximum serum concentration (Cmax), the time to reach Cmax, and the bioavailability (52.98 +/- 6.60 micrograms/ml, 6.8 +/- 1.1 h, 59.7 +/- 12.1%, respectively, vs. 40.04 +/- 13.19 micrograms/ml, 6.0 +/- 1.4 h, 49.0 +/- 18.6 for SPR). The remaining two groups of piglets received medicated feed with either SPR or PMX during a 3-day period both with restrictive (twice-daily) or ad libitum feeding according to a cross-over design. In all four cases, potentially efficacious plasma SDM concentrations between 50 and 150 micrograms/ml were obtained within 24 h after initiation of the treatment. With PMX, plasma concentrations tended to be higher than with SPR with both feeding regimens. Ad libitum feeding was associated with a significantly higher food intake and hence a higher SDM intake resulting in higher plasma concentrations. Additionally, plasma concentrations were more constant over time with ad libitum feeding whereas they declined considerably between meals in restrictively fed animals. In vitro dissolution tests of the two types of medicated feed revealed that SDM was rapidly released from SPR (58% within 15 min) and that SDM release from PMX was markedly slower (3% within 15 min). Despite the relatively slow rate of in vitro dissolution, in vivo absorption of SDM was satisfactory. It is concluded that both forms of SDM medicated feed may be considered bioequivalent and potentially efficacious in piglets.

The excretion of Eimeria oocysts, the faecal dry matter and the weight gain of three groups of 12 calves, were compared during their first 20 days of grazing on a pasture known to have been contaminated with oocysts of Eimeria alabamensis during the previous year. On the day of turnout (day 0) the calves in group 1 were each treated with one bolus per 200 kg bodyweight containing 1.6 g baquiloprim and 14.4 g sulphadimidine. The calves of group 2 received the same treatment on day 3, and the calves of group 3 were left untreated. Eleven of the untreated calves developed clinical coccidiosis due to E. alabamensis and excreted more than 850,000 oocysts/g of faeces 8-10 days after turnout. Seven of the calves in group 1 and five of those in group 2 developed diarrhoea, but it was milder and/or less persistent than in the untreated calves. The treated calves excreted significantly fewer oocysts and lost significantly less weight than the untreated calves. On day 21 all the calves were housed and on day 27 they were challenged with 10 million sporulated oocysts of E. alabamensis and turned out on to the same pasture. Only minor clinical signs were observed in some of the calves, indicating development of immunity in all groups. However, there was a tendency for the calves treated on day 3 to excrete more oocysts and to gain less weight than the other calves.

The kinetics of free and microgranulated sulfadimidine were compared in milk-fed calves dosed orally (180 mg/kg) in a crossover study. Microgranulation results in delayed absorption of sulfadimidine and poor bioavailability, with the area under the plasma concentration-time curve (AUC(0-infinity)) reduced from 7400 to 3781 micrograms.h/mL, and maximum plasma concentration (Cmax) reduced from 188.1 +/- 39.0 to 84.41 +/- 22.6 micrograms/mL. It is concluded that sulfadimidine microgranulated with long chain fatty acids is not suitable for use in milk-fed calves; the gastrointestinal transit time is too rapid to allow full release of the drug, markedly limiting its bioavailability. In adult animals, or in the young of other animal species in which digesta transit time is slower than in calves, the bioavailability of microgranulated sulfadimidine may be much greater.

The interaction of sulphamethazine (SMZ) with pig plasma proteins and albumin was studied by ultrafiltration and equilibrium dialysis. Binding to pig plasma proteins was monophasic (affinity approximately 9.0 mol/L x 10(3)) and the main binding protein was albumin. At 37 degrees C and pH 7.4, the affinity of SMZ for albumin was about 8.0 mol/L x 10(3) and the number of binding sites was estimated as 1.4. Increasing the temperature from 4 to 45 degrees C resulted in a seven-fold decrease in affinity, and increasing pH from 6.0 to 8.0 enhanced affinity for pig albumin ten-fold. The free energy of binding (-delta G) and enthalpy change (-delta H) were around 5.5 and 5.1 Kcal/mol, respectively. The total entropy change (delta S) was small and positive, around 2 cal/mol/degree K. Studies with the fluorescent probes warfarin and dansylsarcosine, suggest that these bind to separate sites on porcine albumin. SMZ displaced both probes and inhibited the deacetylation of p-nitrophenyl acetate by pig albumin. We conclude that: (1) binding of SMZ to pig plasma proteins and albumin is weak; (2) the interaction with albumin is exothermic and enthalpy driven, and (3) pig albumin, like other mammalian albumins, appears to possess discrete binding sites for warfarin and dansylsarcosine. SMZ interacts with both these loci.

The production of stable homogeneous reference materials containing the antimicrobial agent sulphadimidine in pig tissue is described. These were commissioned by the Community Bureau of Reference (BCR), established by the Commission of the European Communities, to promote improvements in analytical accuracy and to ensure uniformity of results determined by member states. Sulphadimidine-containing tissue powders (400 vials each of muscle, liver and kidney) were prepared by orally dosing pigs with drug, producing lyophilized tissue powders and blending these with negative tissues from unmedicated animals to achieve target concentrations. Details of the production process, the stabilizing procedure developed and the analytical assessments of homogeneity and stability are given.

The concentration of sulfadimidine was measured in the urine of pigs which were housed (over five days) in boxes where other pigs have been treated orally with sulfadimidine before. Sulfadimidine was measured in the urine of the unmedicated pigs in a concentration of up to 4 micrograms/ml. Considering these urine concentrations, violative sulfadimidine tissue residues would be expectable in the carcass after slaughter. The practice of fixing withdrawal times must be considered again to ensure that drug residues in tissues are below the MRL before slaughter also in unmedicated animals.

Sulfamethazine (SMZ) ip administration for 3 d to chickens showed significant induction of cytochrome P-450 levels and in the activities of aminopyrine N-demethylase, aniline hydroxylase and glutathione s-transferase at the dosage of 150 mg SMZ/kg body weight. Cytochrome P-450 and the activity of aniline hydroxylase were significantly decreased at 300 mg SMZ/kg body weight when compared to 150 mg SMZ/kg body weight. Other doses produced no significant changes in the parameters studied. One hundred fifty mg SMZ/kg for 1 or 3 d caused significant induction of cytochrome b5, cytochrome P-450, the drug metabolizing enzymes and glutathione s-transferase; however, 5 d of SMZ produced no significant changes. The in vitro 10 mM SMZ inhibition of aminopyrine N-demethylase and aniline hydroxylase and the induction of enzymes at 150 mg SMZ/kg body weight indicates that SMZ is a substrate of the mixed function oxidase system and may be an inducer of specific forms of cytochrome P-450.

The effectiveness of a feed-additive antimicrobial combination for improving feedlot performance and health was tested using 4325 high-risk feeder calves randomly allocated to a control group or an experimental group. The experimental group received the conventional ration plus a feed additive containing 700 mg per head/day of chlortetracycline and sulfamethazine from arrival at the feedlot to day 56 of the feeding period. The inclusion of the feed additive to the ration significantly improved average daily gain for days 0-28 (P = 0.0163) and 0-56 (P = 0.0001), and the feed conversion for days 0-28 (P = 0.0061) and 0-56 (P = 0.0004). Additionally, the use of the feed additive significantly reduced the rate of bovine respiratory disease morbidity for days 0-28 (P = 0.0014) and 0-56 (P = 0.0001), the rate of relapses and mortality for days 0-56 (P = 0.0151 and P = 0.0209, respectively), and the rate of animals diagnosed with chronic respiratory disease for days 0-28 and 0-56 (P = 0.0009 and P = 0.0002, respectively). Performance and health improvements produced by the use of the feed additive were cost-effective.

Cows were dosed orally (n = 4) or intravenously (n = 4) with sulfamethazine [sulmet; 4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzenesulfonamide] for 5 consecutive days (220 mg/kg of body weight on day 1 and 110 mg/kg on days 2-5). The concentrations of sulmet, N4-acetylsulfamethazine (Ac-sulmet), and the N4-lactose conjugate of sulfamethazine (lac-sulmet) were measured in milk and blood collected at 24 h intervals after the last doses of sulmet were given. The method of analysis included (1) spiking of samples with known amounts of 13C6-labeled reference compounds, (2) resolution of the 3 compounds by reversed-phase chromatography, (3) hydrolysis of lacsulmet, (4) treatment with diazomethane to yield N1-methyl derivatives, and (5) gas chromatography/mass spectrometry. The ratios of intensities of selected mass spectral ions containing 12C6 and the corresponding ions containing 13C6 were used for residue quantitation. Sulmet, which was always the most abundant residue in the blood, decreased to less than 100 ppb 4 days after the last doses were given and to less than 10 ppb 7 days after the last doses. The concentrations of sulmet in milk were approximately one fifth the concentrations of sulmet in blood. The concentrations of lac-sulmet and Ac-sulmet in milk were lower than the concentrations of sulmet in milk.

After administration of a bolus containing 0.8 g baquiloprim and 7.2 g sulphadimidine to six calves, plasma concentrations of these compounds exceeded MICs for Pasteurella haemolytica from about 3 hours to at least 48 hours. Experimental infection of three calves with 2.8 x 10(10) P. haemolytica type A1 organisms by the endobronchial route resulted in extensive pneumonic lesions, and smaller, similar lesions were found post mortem in two other calves which had received the same inoculum. Nine similar calves were also infected in the same manner after dosing six hours previously with a bolus providing doses of 4 mg/kg baquiloprim and 36 mg/kg sulphadimidine. Four of these calves received a second bolus 48 hours later. In contrast to the undosed calves, the treated calves exhibited few symptoms of respiratory disease following infection, and their temperatures remained normal. The mean temperatures of the control calves were significantly elevated for several days after infection. At post mortem examinations 6 days after infection, lung lesions were insignificant in all the dosed calves. P. haemolytica was isolated from the lungs of all 5 control calves but not from any treated animal. The combined dose of 40 mg/kg baquiloprim and sulphadimidine was the minimum recommended for use of the bolus in the field, and the results therefore predict efficacy when used in outbreaks of respiratory infection in calves associated with this organism.

Effects of recombinant bovine somatotrophin (rBST) on in vivo and in vitro oxidative drug metabolism were studied in male rats. rBST was given subcutaneously at a dose of 250 or 500 micrograms 100 g-1 bodyweight 24 h-1 in different dosage patterns. Sulphadimidine (SDD) plasma clearance, urinary excretion of 6-hydroxy-SDD and the in vitro microsomal SDD-hydroxylations were only inhibited when rBST was given in three injections per 24 hours. The hepatic microsomal ethylmorphine N-demethylation rate and the testosterone hydroxylation rate at the 6 beta position were significantly reduced after one rBST injection per 24 hours. Microsomal testosterone hydroxylation rates at the 16 alpha and 2 alpha-positions were reduced depending on the frequency of rBST administration. It is concluded that the inhibition of in vivo and in vitro drug oxidation in rats by rBST is associated with selective changes in activity of cytochrome P450 enzymes in the liver.

The elimination into bovine milk of sulphonamides (sulphadimidine and sulphamethoxypyridazine) and dapsone following intramammary infusion was studied. Determination of sulphonamides and dapsone in milk was performed by a high performance liquid chromatographic method with UV detection. The limit of quantification was 0.01 microgram/ml. Withdrawal times were established considering the maximum residue limits fixed by the European Community (100 micrograms/kg for sulphonamides and 25 micrograms/kg for dapsone). The diffusion of residues into milk from a quarter infused by the intramammary route to the untreated quarters was also studied.

Concentration of sulfamethazine was measured in plasma and tissues (fat, liver, kidney, spleen, lungs, and skeletal muscle) of pigs given the drug IV and PO. The plasma concentration vs time curve was best described by a 2-compartment model, with a distribution half-life of 0.46 hour and an elimination half-life of 16.9 hours. Bioavailability after oral administration was 85.8 +/- 5.3%. The tissue and plasma sulfamethazine concentration vs time data were used to develop a multi-compartment pharmacokinetic model of sulfamethazine disposition in pigs. Plasma and tissue concentrations of sulfamethazine in pigs were measured at various intervals after multiple oral doses of sulfamethazine, and were compared to concentrations predicted by the model. Model predictions for tissue concentrations of sulfamethazine after addition of the drug to feed (110 micrograms/g of feed for 98 days; 550 micrograms/g for 30 days) were compared to results from other studies. The model accurately predicted the number of days for sulfamethazine concentration to fall below 0.1 micrograms of tissue/g (0.1 ppm, the tolerated concentration) in various tissues.

Prostaglandins are known to interfere with drug metabolizing processes. Nocloprost (9 beta-chloro-16,16-dimethyl PG E2) is a promising new cytoprotective prostaglandin in clinical evaluation for the treatment of ulcer disease and prophylaxis of gastric lesions caused by NSAID. Pharmacokinetic interactions of 400 micrograms nocloprost with 15 mg/kg antipyrine and 500 mg sulfamethazine (all given p.o.) were studied with a controlled, single-blind crossover trial in 16 healthy male volunteers (age 22-25 years, body weight 63-94 kg, body height 175-187 cm) in order to measure potential interferences with oxidative and conjugative drug metabolism. All individuals were extensive metabolizers of debrisoquine, 9 were slow and 7 rapid acetylators of sulfamethazine. Antipyrine and its major metabolites were measured in serum respectively, urine with the HPLC-method, sulfamethazine and its acetylated metabolite with a colorimetric technique. Nocloprost premedication (30 min prior to the test drugs) did neither interfere significantly with the oxidative processes involved in the disposition of antipyrine nor with the N-acetylation of sulfamethazine. Higher metabolic and renal clearance values of sulfamethazine in slow acetylators were most likely the result of the affected drug absorption. Nocloprost significantly reduced absorption rates of antipyrine and sulfamethazine in the group of slow but not of rapid acetylators. The extent of bioavailability remained unchanged. This phenomenon was certainly caused by the effects of the cytoprotective prostaglandin on those gastrointestinal functions which are determinants of drug absorption.

Four Holstein steers (164 kg) with cannulas in the rumen and proximal duodenum were used to evaluate the effects of oral antibiotic administration on characteristics of digestion of a 71% concentrate diet. Treatments were as follows: 1) no antibiotic; 2) 350 mg.steer-1.d-1 of chlortetracycline (CTC) provided in the feed (A350); 3) 350 mg.steer-1.d-1 of CTC plus 350 mg.steer-1.d-1 of sulfamethazine provided in the feed (AS700); 4) 22 mg of CTC/kg BW (3.6 g.steer-1.d-1) provided in the drinking water (A3600). Drinking water intake averaged 23.5 L/d and was not affected (P > .10) by treatments. Antibiotic treatments increased passage (P < .05) of OM to the small intestine. This effect was largely due to decreased (27%, P < .05) ruminal ADF digestion. Passage of nonammonia N to the small intestine was greater (10.4%, P < .01) for A3600 vs A350 and AS700; the latter was similar to the control. This effect was due to an increased (23.4%, P < .05) synthesis of microbial N. Total tract digestion of OM (P < .05), starch (P < .05), N (P < .10), and DE (P < .10) were slightly lower (2.7, 1.6, 2.8, and 2.7%, respectively) for antibiotic-supplemented diets. Total tract starch (P < .10) and N (P < .01) digestion were further decreased (1.2 and 3.5%, respectively) for A3600 vs A350 and AS700. Postruminal digestion of ADF was greater (131%, P < .10) for antibiotic-supplemented diets, compensating for the lower ruminal digestion. There were no treatment effects (P > .10) on ruminal pH.(ABSTRACT TRUNCATED AT 250 WORDS)

A cocktail of four model substances orally administered to humans is used for simultaneous characterization of phenobarbital and 3-methylcholanthrene inducible forms of cytochrome-P450 and two genetic polymorphisms, the debrisoquine hydroxylation and N-acetylation. The investigations offer the possibility to assess four main processes of hepatic drug metabolism as well as the judgement of alterations in drug elimination. Both acetylation and hydroxylation phenotypes are not influenced after administration of the cocktail compared to the administration of the substances alone. A statistically significant 30.4% increase of mean body residence time could be found only for monomethylaminoantipyrine. The other pharmacokinetic parameters of monomethylaminoantipyrine and caffeine were unchanged. A one-point-determination for the 9 hour serum concentrations of monomethylaminoantipyrine, caffeine and sulfamethazine/acetylsulfamethazine as well as the 0-9 hours urine concentrations of debrisoquin/4-hydroxydebrisoquin will be conceivable by using "normal ranges".

The pharmacokinetics of antipyrine and sulphadimidine were studied in male camels, sheep and goats. The two drugs were administered concomitantly. Following intravenous injection of antipyrine (25 mg/kg) and sulphadimidine (sulfamethazine) (100 mg/kg), the pharmacokinetics of the two drugs were adequately described by a one-compartment model. Antipyrine half-life in goats (2.58 h) was shorter than that in sheep (4.04 h) and camels (18.78 h). The plasma clearance was greatest in goats then sheep and then camels. For sulphadimidine, a significantly greater volume of distribution was observed in camels and the greatest plasma clearance and shortest half-life were reported in goats. Sulphadimidine half-life was 2.77 h in goats, 4.72 h in sheep and 7.36 h in camels. The present results suggest that goats have the fastest elimination of these drugs from the circulation, followed by sheep and then camels.

The effect of different doses of sulphadimidine (250, 500, 750 and 1000 mg) on acetylation capacity in 10 normal individuals was investigated in a randomized cross-over study design. The subjects were initially phenotyped with an oral dose of 750 mg of sulphadimidine. Four weeks later, each subject was assigned four different doses of sulphadimidine. The acetylator phenotype was classified for each dose as rapid if the percentage of acetylated sulphadimidine in the post-dose 5-6 hour urine is more than 70% and as slow if less than 70%. The results indicate a clear separation into two phenotypes, even with the smallest dose of the drug. A slow acetylator in the 10 subjects showed a saturation of the acetylation capacity with increasing doses. This trend was not observed in the remaining subjects who were identified as rapid acetylators regardless of the doses. An oral dose of 750 mg of sulphadimidine is suggested as a 'standard' or optimum dose for acetylator phenotype testing.