Pharmacokinetics of sulphadimidine in carp (Cyprinus carpio L.) and rainbow trout (Salmo gairdneri Richardson) acclimated at two different temperature levels

The influence of temperature (10 degrees C and 20 degrees C) on pharmacokinetics and metabolism of sulphadimidine (SDM) in carp and trout was studied. At 20 degrees C a significantly lower level of distribution (Vdarea) and a significantly shorter elimination half-life (T(1/2)beta) was achieved in both species compared to the 10 degrees C level. In carp the body clearance parameter (ClB(SDM)) was significantly higher at 20 degrees C compared to the value at 10 degrees C, whereas for trout this parameter was in the same order of magnitude for both temperatures. N4-acetylsulphadimidine (N4-SDM) was the main metabolite of SDM in both species at the two temperature levels. The relative N4-SDM plasma percentage in carp was significantly higher at 20 degrees C than at 10 degrees C, whereas there was in trout no significant difference. In neither species was the peak plasma concentration of N4-SDM (Cmax(N4-SDM)) significantly different at two temperatures. The corresponding peak time of this metabolite (Tmax(N4-SDM)) was significantly shorter at 20 degrees C compared to 10 degrees C in both carp and trout. In carp at both temperatures, acetylation occurs to a greater extent than hydroxylation. Only the 6-hydroxymethyl-metabolite (SCH2OH) was detected in carp, at a significant different level at the two temperatures. Concentrations of hydroxy metabolites in trout were at the detection level of the HPLC-method (0.02-micrograms/ml). The glucuronide metabolite (SOH-gluc.) was not detected in either species at the two temperatures.     

Pharmacokinetics of sulfadimidine and its N4-acetyl metabolite in healthy and diseased rabbits infected with Pasteurella multocida

The pharmacokinetics of sulfadimidine (SDM) and its N4-acetyl metabolite (N4SDM) were investigated after intravenous bolus injection of a single dose (200 mg/kg) of SDM in normal and diseased New Zealand white rabbits. The apparent distribution volume at steady state, total body clearance and elimination half-life of SDM in normal animals were 0.7 +/- 0.3 l/kg, 0.57 +/- 0.24 l/kg/h and 1.6 +/- 1.3 h, respectively. Of the administered dose, 62.1% was metabolized by N4-acetylation, and 12.7 +/- 1.1 and 2.8 +/- 1.8% of the dose was excreted as free drug by the kidney and gastrointestinal tract, respectively. The 'apparent' formation and elimination half-lives of N4SDM were 0.6 +/- 0.4 and 2.2 +/- 1.1 h, respectively. The metabolite was eliminated mainly by excretion through the kidney. There was no significant effect of acute pasteurellosis on the pharmacokinetics of either SDM or N4SDM in rabbits.     

Pharmacokinetics, renal clearance, tissue distribution, and residue aspects of sulphadimidine and its N4-acetyl metabolite in pigs

Pharmacokinetics and tissue distribution experiments were conducted in pigs to which sulphadimidine (SDM) was administered intravenously, orally, and intramuscularly at a dosage of 20 mg SDM/kg. SDM was acetylated extensively, but neither hydroxy metabolites nor their derivatives could be detected in plasma, edible tissues or urine. Following i.v. and two oral routes of administration, the N4-acetylsulphadimidine (N4-SDM) concentration-time curve runs parallel to that of SDM. The percentage of N4-SDM in plasma was in the range between 7 and 13.5% of the total sulphonamide concentration. The bioavailability of SDM administered in a drench was 88.9 +/- 5.4% and administered mixed with pelleted feed for 3 consecutive days it was 48.0 +/- 11.5%. The renal clearance of unbound SDM, which was urine flow related, was 1/7 of that of creatinine, indicating reabsorption of the parent drug. The unbound N4-SDM was eliminated three times faster than creatinine, indicating that tubular secretion was the predominant mechanism of excretion. After i.v. administration, 51.9% of the administered dose was recovered in urine within 72 h p.i., one quarter of which as SDM and three quarters as N4-SDM. Tissue distribution data obtained at 26, 74, 168, and 218 h after i.m. injection revealed that the highest SDM concentration was found in plasma. The SDM concentration in muscle, liver, and kidney ranged from one third to one fifth of that in plasma. The N4-SDM formed a minor part of the sulphonamide content in edible tissues, in which the SDM as well as the N4-SDM concentration parallelled the plasma concentrations. Negative results obtained with a semi-quantitative bioassay method, based on monitoring of urine or plasma, revealed that the SDM concentration levels in edible tissues were in that case below 0.1 mu/g tissue.     

The role of plasma protein binding on the metabolism and renal excretion of sulphadimethoxine and its metabolite N4-acetylsulphadimethoxine in pigs

The effects of plasma protein binding on the elimination of sulphadimethoxine (SDM) were examined after intravenous administration of 6.25, 12.5, 25, 50, 100 and 150 mg/kg to pigs. At an early stage of the experiment, the animals were anaesthetised by inhalation of enflurane to obtain a more exact relationship between plasma concentration and the renal excretion. SDM and its acetylated conjugate, N4-acetylsulphadimethoxine (N4-SDM) were detected in plasma and urine of all animals, and the recovery of the doses was almost complete in two animals with negligible renal excretion of SDM. The percentages of plasma protein binding of SDM and N4-SDM were almost similar, and ranged from 30 to 95%, depending on the plasma concentration. The metabolic clearance of SDM by acetylation increased when the plasma protein binding decreased. These results suggested that the main elimination route of SDM in pigs is acetylation, and that the plasma protein binding can have a large effect on the elimination of SDM in pigs. The effect of plasma protein binding on the renal clearance of SDM was not so evident, because urine pH had a much greater effect on it. The deacetylation of N4-SDM was detected after 25 mg/kg intravenous administration of N4-SDM, which suggests that the metabolic clearance of SDM is part of an acetylation-deacetylation equilibrium. Saturation of the active tubular reabsorption of SDM and of the active tubular secretion of N4-SDM was also suggested after higher doses of SDM.     

Pharmacokinetics and metabolism of sulphadimidine in kids at 12 and 18 weeks of age

The pharmacokinetics and metabolism of sulphadimidine (SDM) following intravenous administration of 100 mg/kg were studied in seven dwarf preruminant kids at 12 weeks of age, and again at the ruminant stage, when the animals were 18 weeks old. The persistence of SDM in 18-week-old kids was prolonged in comparison to the 12-week-old animals: a lower total body clearance and a prolonged elimination of SDM were obtained in the older animals. The renal clearance values of SDM and its metabolites were the same at both ages. The decrease of SDM clearance is related to the significant reduction in SDM hydroxylation at the older age. The reduced oxidative hepatic metabolism may result from the sexual maturation of the kids.     

Nonlinear pharmacokinetics of intravenous sulphadimethoxine and its dosage regimen in pigs

The time courses of the total (Ct) and unbound plasma (Cf) concentration after the i.v. injection of 20, 50 and 100 mg/kg of sulphadimethoxine (SDM) were examined in pigs. The area under the Ct-time curve per unit dose decreased dose-dependently. Vdarea and total body clearance of Ct increased dose-dependently. The concentration-dependent plasma protein binding of SDM was evident after 50 and 100 mg/kg. The time courses of Cf en Ct after 3 doses were analyzed by a one compartment open model with nonlinear plasma protein binding. The agreement between calculated curves of Cf and Ct and the observed values, and relative constancy of pharmacokinetic parameters were obtained over 3 doses. These results suggested that the nonlinear pharmacokinetics of SDM was caused by saturable plasma protein binding. The multiple i.v. dose of SDM was based on the dosage regimen using the nonlinear pharmacokinetic model (50 mg/kg, 24 hour interval, 4 days). The observed Cf was maintained in the intended range by the dosage regimen. Therefore, the dosage regimen based on the nonlinear pharmacokinetics may allow the unbound concentration after i.v. injection of SDM in pigs to be controlled.     

Nonlinear pharmacokinetics of intravenous sulphadimethoxine and its dosage regimen in pigs

Summary

The time courses of the total (Ct) and unbound plasma (Cf) concentration after the i.v. injection of 20, 50 and 100 mg/kg of sulphadimethoxine (SDM) were examined in pigs;

The area under the Ct‐time curve per unit dose decreased dose‐dependently. Vd_area and total body clearance of Ct increased dose‐dependently.

The concentration‐dependent plasma protein binding of SDM was evident after 50 and 100 mg/kg.

The time courses of Cf en Ct after 3 doses were analysed by a one compartment open model with nonlinear plasma protein binding. The agreement between calculated curves of Cf and Ct and the observed values, and relative constancy of pharmacokinetic parameters were obtained over 3 doses. These results suggested that the nonlinear pharmacokinetics of SDM was caused by saturable plasma protein binding.

The multiple i.v. dose of SDM was based on the dosage regimen using the nonlinear pharmacokinetic model (50 mg/kg, 24 hour interval, 4 days). The observed Cf was maintained in the intended range by the dosage regimen. Therefore, the dosage regimen based on the nonlinear pharmacokinetics may allow the unbound concentration after i.v. injection of SDM in pigs to be controlled.     

Pharmacokinetics,renal clearance,tissue distribution,and residue aspects of sulphadimidine and its N4‐acetyl metabolite in pigs

Summary

Pharmacokinetics and tissue distribution experiments were conducted in pigs to which sulphadimidine (SDM) was administered intravenously, orally, and intramuscularly at a dosage of 20 mg SDM/kg. SDM was acetylated extensively, but neither hydroxy metabolites nor their derivatives could be detected in plasma, edible tissues or urine. Following i.v. and two oral routes of administration, the N₄‐acetylsulphadimidine (N₄‐SDM) concentration‐time curve runs parallel to that of SDM. The percentage of N₄‐SDM in plasma was in the range between 7 and 13.5% of the total sulphonamide concentration. The bioavailability of SDM administered in a drench was 88.9 ± 5.4 % and administered mixed with pelleted feed for 3 consecutive days it was 48.0 ± 11.5 %. The renal clearance of unbound SDM, which was urine flow related, was 1/7 of that of creatinine, indicating reabsorption of the parent drug. The unbound N₄SDM was eliminated three times faster than creatinine, indicating that tubular secretion was the predominant mechanism of excretion.

After i.v. administration, 51.9 % of the administered dose was recovered in urine within 72 h p.i., one quarter of which as SDM and three quarters as N₄‐SDM.

Tissue distribution data obtained at 26, 74, 168, and 218 h after i.m. injection revealed that the highest SDM concentration was found in plasma. The SDM concentration in muscle, liver, and kidney ranged from one third to one fifth of that in plasma. The N₄‐SDM formed a minor part of the sulphonamide content in edible tissues, in which the SDM as well as the N₄‐SDM concentration parallelled the plasma concentrations.

Negative results obtained with a semi‐quantitative bioassay method, based on monitoring of urine or plasma, revealed that the SDM concentration levels in edible tissues were in that case below 0. 1μ/g tissue.     

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.     

Disposition of sulfadimidine and its N4-acetyl and hydroxy metabolites in horse plasma

The plasma disposition of sulfadimidine (SDM) and its metabolites N4-acetylsulfadimidine (N4-SDM), 6-hydroxymethyl-4-methyl-pyrimidine (SCH2OH) and 5-hydroxy-4,6-dimethyl-pyrimidine (SOH), was studied in three horses following intravenous administration of SDM at dose levels of 20 and 200 mg/kg in cross-over trials. The percentages of N4-SDM (0.58-0.90%), SOH (0.83-6.75%) and SCH2OH (0.38-0.71%) in plasma, expressed as a percentage of the total sulfonamide concentration, were small and their plasma concentrations were parallel with SDM from 4 h following administration. At high doses (200 mg/kg), the elimination half-life was slightly longer than at low doses (6.0, 10.5, 11.0 vs 5.0, 9.5, 9.5, respectively). The plasma protein binding was related to the dose; it was for the 20 and 200 mg/kg doses, respectively:SDM:61.5-73.3% and 50.5-52.1%; SOH: 47.1-71.0% and 36.7-39.5%, and for N4-SDM: 45.9-63.2% and 38.3-53.7%. The protein binding for SCH2OH, measured in samples obtained at the high dose level, ranged from 13.8 to 20.0%.     

Pharmacokinetics and body fluid and endometrial concentrations of ormetoprim-sulfadimethoxine in mares.

Six healthy adult mares were each given an oral loading dose of ormetoprim(OMP)-sulfadimethoxine (SDM) at a dosage of 9.2 mg of OMP/kg and 45.8 mg of SDM/kg, followed by four maintenance doses of 4.6 mg of OMP/kg and 22.9 mg of SDM/kg, at 24 h intervals. Ormetoprim and SDM concentrations were measured in serum, synovial fluid, peritoneal fluid, cerebrospinal fluid, urine and endometrium. The highest mean serum OMP concentration was 0.92 micrograms/mL 0.5 h after the first dose; the highest mean SDM concentration was 80.9 micrograms/mL 8 h after the first dose. The highest mean synovial fluid concentrations were 0.14 microgram of OMP/mL and 28.5 micrograms of SDM/mL 12 h after the first dose. The highest mean peritoneal fluid concentrations were 0.19 micrograms of OMP/mL 6 h after the first dose and 25.5 micrograms of SDM/mL 8 h after the fifth dose. The highest mean endometrial concentrations were 0.56 micrograms of OMP/g and 28.5 micrograms of SDM/g 4 h after the fifth dose. The mean cerebrospinal fluid concentrations were 0.08 micrograms of OMP/mL and 2.1 micrograms of SDM/mL 5 h after the fifth dose. Mean trough urine drug concentrations were greater than or equal to 0.4 micrograms of OMP/mL and greater than or equal to 172 micrograms of SDM/mL. Two of the mares were each given a single intravenous (IV) injection of OMP and SDM at a dosage of 9.2 mg of OMP/kg and 45.8 mg of SDM/kg. Excitation and muscle fasciculations were observed in both mares after IV administration and all scheduled blood samples could be collected from only one of the two mares.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma/muscle ratios of sulfadimethoxine residues in channel catfish (Ictalurus punctatus)

Channel catfish ( n = 84) maintained at a water temperature of 27°C were used in a feeding study to determine the plasma to muscle concentration ratios of sulfadimethoxine (SDM) and 4-N-acetylsulfadimethoxine residues. Sulfadimethoxine medicated feed was provided free choice at 42 mg SDM/kg body weight once daily for 5 days and the plasma and muscle concentrations of SDM were determined at selected withdrawal times (6, 12, 24, 48, 72, and 96 hours) following the last dose. Considerable variation in total SDM tissue concentration among fish within a sampling period was observed. For fish ( n = 12) at six hours post-dose, total SDM concentrations ranged from 1.4–24.8 μg/mL and 0.6–12.6 μg/g, with mean total SDM concentrations of 9.1 μg/mL and 5.3 μg/g for plasma and muscle, respectively. However, a mean plasma:muscle concentration ratio of 1.8:1 ± 0.3:1 was obtained over all concentrations and sampling periods. The plasma:muscle 95% t distribution interval for individual fish was 1.2:1 to 2.4:1. A correlation coefficient of 0.967 was obtained for the relationship between plasma and muscle total SDM concentration among individual fish ( n = 25). Results of this study indicate that plasma total SDM concentration may be used to identify samples containing violative SDM muscle residue. No fish contained total SDM muscle residues greater than the FDA tolerance (0.1 μg/g) by 48 hours following the final dose.     

Plasma disposition and renal clearance of sulphadimidine and its metabolites in laying hens

Plasma disposition of sulphadimidine (SDM) and its metabolites was studied in laying hens after 100 mg SDM kg-1 doses were administered as a single intravenous dose, a single oral dose and multiple oral doses once daily for five consecutive days. SDM was extensively metabolised by acetylation and hydroxylation. In plasma, the metabolite observed with the highest concentration was N4-acetylsulphadimidine (N4-SDM) followed by hydroxymethylsulphadimidine (CH2OH) and 5-hydroxysulphadimidine. Following intravenous administration a biphasic elimination (as seen for a capacity limited reaction) pattern for SDM and its metabolites was observed. Multiple (5x) SDM dosing revealed plasma SDM concentrations ranging between 7 and 108 micrograms ml-1; within 96 hours of termination of the multiple SDM dosing, the plasma SDM concentration was below 0.01 micrograms ml-1. The renal clearances of N4-SDM and the hydroxy metabolites were approximately 10 times greater than that of SDM. The SDM mass balance (faecal/urinary recovery) showed a loss of 56 per cent after intravenous dosage and of 67 per cent after a single oral dosage; the hydroxy metabolites accounted for the highest percentage in faeces/urine. Thus additional metabolic pathways must exist in laying hens.     

Pharmacokinetics and renal clearance of sulphadimidine, sulphamerazine and sulphadiazine and their N4-acetyl and hydroxy metabolites in pigs

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

Dose dependent disposition of sulphadimidine and of its N4-acetyl and hydroxy metabolites in plasma and milk of dairy cows

The disposition of sulphadimidine (SDM) and of its N4-acetyl (N4-SDM) and two hydroxy metabolites, 6-hydroxymethyl-(SCH2OH) and 5-hydroxyasulphadimidine (SOH), was studied in plasma and milk of dairy cows following intramuscular or intravenous administration of sulphadimididine-33.3% at doses of 10, 45, 50, and 100 mg/kg. The main metabolite in plasma as well as in milk was SCH2OH. The metabolite percentages, the final plasma elimination half-lives, and the time of peak SDM concentrations in milk are presented for different dosages. The concentrations of SDM and its metabolites in milk ran parallel to those in plasma beyond 4 hours p.i. The metabolite concentrations in plasma and milk were lower than those of the parent SDM. Sulphate and glucuronide metabolites could not be detected in milk. At high doses (45 mg/kg or more) and SDM plasma concentrations exceeding 20 micrograms/ml, a capacity limited metabolism of SDM to SCH2OH was noticed, viz. a steady state concentration of SCH2OH and a biphasic elimination pattern for SDM and SCH2OH in plasma and milk. The mean ultrafiltrate ratios of the milk to plasma concentrations with respect to SDM, SCH2OH, SOH, and N4-SDM were: 0.69, 0.22, 020, and 0.63, respectively. The total amount of SDM and its metabolites recovered from the milk after milking twice daily over the whole experimental time was less than 2% of the applied dose. A bioassay method allowed of detecting qualitatively SDM concentrations exceeding 0.2 micrograms/ml in plasma or milk. Withholding times for edible tissues and milk are suggested.     

Pharmacokinetics, bioavailability and dosage regimen of sulphadimidine in camels (Camelus dromedarius) under hot, arid environmental conditions

A two-way crossover study was conducted in young Bikaneri camels (aged between 12 and 18 months) during the hot summer season to determine the bioavailability, pharmacokinetics and dosage regimens of sulphadimidine (SDM). A dose of 100 mg.kg-1 of SDM was used to study both the intravenous and oral pharmacokinetics of the drug. Analysis of the intravenous data according to a two-compartment pharmacokinetic model revealed that SDM was well distributed in the body (Vd(area):0.862 L.kg-1), had an overall body clearance of 0.035 +/- 0.019 L.h-1.kg-1 and the elimination of half-lives was in the range of 14.2 to 20.6 h. The mean maximum plasma SDM concentration following oral administration was 63.23 +/- 2.33 micrograms.mL-1, which was achieved 24 h after the oral administration. The mean bioavailability of SDM following oral administration was approximately 100%. To achieve and maintain the therapeutically satisfactory plasma sulphadimidine levels of > or = 50 micrograms.mL-1, the optimum dosage regimen for camels following either intravenous or oral administration would be 110 mg.kg-1 as the priming dose and 69 mg.kg-1 as the maintenance dose, to be repeated at 24 h intervals.     

Effect of age on the acetylation and deacetylation reactions of sulphadimidine and N4- acetylsulphadimidine in calves

Following intravenous (i.v.) or intramuscular (i.m.) adminstration of sulphadimidine (SDM), the pharmacokinetics of SDM and N₄-acetylsulphadimidine (N₄-SDM) were studied in plasma of calves from the first day of life to the age of about 6 months. An obvious age dependency was observed for the elimination half-life (t1/2) of SDM: the first day of life the t1/2 ranged between 13.5 and 17 h, and decreased in approximately 3 weeks to 4–6 h and remained constant from this time. The metabolite N₄-SDM, as a percentage of the total concentration of the sulphonamide measured in plasma of neonatal calves, ranged between 21.6 and 25.5% at the first day of life, declined in 3 weeks to approximately 12.8%, and at 5 till 9 weeks the final percentage was about 6.8%. Following administration of N₄-SDM, the elimination half-life of N₄-SDM was 3 h in an 8-day-old calf declined to 1.4–1.7 h in 4-week-old calves, and was 0.9 h in calves older than 11 weeks. The percentage of SDM (a metabolite of N₄-SDM) in plasma increased with time after injection from 5.5 to 62.8% of the total sulphonamide plasma concentration. This value was age-related. The total body clearance of N₄-SDM was three- to five-fold higher than that of SDM.     

Pharmacokinetics and renal clearance of sulphadimidine,sulphamerazine and sulphadiazine and their N4‐acetyl and hydroxy metabolites in pigs

Summary

The effect of molecular structure on the drug disposition and protein binding in plasma, the urinary recovery, and the renal clearance of sulphamerazine (SMR), sulphadiazine (SDZ), and sulphadimidine (SDM) and their N₄‐acetyl and hydroxy derivatives were studied in pigs. Following IV administration of SDM, SMR and SDZ, their mean elimination half‐lives were 12.4 h, 4.3 h and 4.9 h respectively. The plasma concentrations of parent sulphonamide were higher than those of the metabolites, and ran parallel. The acetylated derivatives were the main metabolites; traces of 6‐hydroxymethylsulphamerazine and 4‐hydroxysulphadiazine were detected in plasma.

The urine recovery data showed that in pigs acetylation is the major elimination pathway of SDM, SMR and SDZ; hydroxylation became more important in case of SMR (6‐hydroxymethyl and 4‐hydroxy derivatives) and SDZ (4‐hydroxy derivatives) than in SDM. In pigs methyl substitution of the pyrimidine side chain decreased the renal clearance of the parent drug and made the parent compound less accessible for hydroxylation. Acetylation and hydroxylation speeded up drug elimentation, because their renal clearance values were higher than those of the parent drug.     

The effect of testosterone and rutting on the metabolism and pharmacokinetics of sulphadimidine in goats

After testosterone pretreatment of castrated goats and during the rutting season of adult entire male goats, the oxidative metabolism of sulphadimidine (SDM) was inhibited markedly compared with the castrated control state of these animals. The oxidation of the 5 position (yielding 5-hydroxysulphadimidine) and of the 6-hydroxymethyl group (yielding 6-carboxysulphadimidine) was decreased equally, with that of the methyl group at the pyrimidine side chain itself being 6-hydroxymethylsulphadimidine (CH2OH), whereas the acetylation pathway was unaffected by testosterone. The consequence of altered metabolism by testosterone was a prolongation of SDM presence in the body. Effects on protein binding of the CH2OH metabolite and on the renal clearance of SDM were also investigated.     

Ormetoprim-sulfadimethoxine in cattle: pharmacokinetics, bioavailability, distribution to the tears, and in vitro activity against Moraxella bovis

The pharmacokinetics, bioavailability, and distribution to the tears of ormetoprim (OMP; 5.5 mg/kg of body weight) and sulfadimethoxine (SDM; 27.5 mg/kg of body weight) were determined following IV or oral administration to 6 Holstein steers. After IV administration, the disposition kinetics of both drugs were best described by a 2-compartment open model. Sulfadimethoxine had a moderately rapid distribution phase, followed by a slower elimination phase, with a mean half-life (t 1/2) of 7.91 hours. The mean volume of distribution of SDM was 185 ml/kg, and the mean body clearance was 0.28 ml/min X kg. The concentration of SDM in tears was lower than the corresponding plasma concentration, and the elimination of SDM from tears (t 1/2 = 3.02 hours) was significantly faster than its elimination from plasma (t 1/2 = 7.91 hours). The disposition of OMP administered IV was characterized by a rapid distribution phase, followed by a rapid elimination phase (t 1/2 = 1.37 hours). The high values of the mean volume of distribution (1,450 ml/kg) and mean rate of body clearance (13.71 ml/min X kg) indicated that OMP was widely distributed in the body and was rapidly cleared from the body. Ormetoprim concentrations in tears exceeded corresponding plasma concentrations, and the elimination of OMP from tears was significantly slower (t 1/2 = 1.91 hours) than from plasma (t 1/2 = 1.37 hours). After oral administration of an OMP-SDM combination in bolus form, the absorption of SDM was slow (absorption t 1/2 = 3.32 hours), but complete.(ABSTRACT TRUNCATED AT 250 WORDS)