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.     

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.     

Pharmacokinetics of sulphamethoxazole in calves and cows

The kinetics of sulphamethoxazole (SMZ) in plasma and milk, and its metabolism, protein binding and renal clearance were studied in three newborn calves and two dairy cows after intravenous administration. SMZ was predominantly acetylated; no hydroxy and glucuronide derivatives could be detected in plasma and urine. Age-dependent pharmacokinetics and metabolism of SMZ were observed. The plasma concentration-time curves of the N4-acetyl metabolite in the elimination phase were parallel to those of the parent drug; the N4-acetyl metabolite plasma percentage depended on age and ranged between 100% (new-born) to 24.5% (cow). SMZ was rapidly eliminated (elimination half-lives: 2.0-4.7 h) and exhibited a relatively small distribution volume (VDarea: 0.44-0.57 l/kg). SMZ was excreted predominantly by glomerular filtration, while its N4-acetyl metabolite was actively eliminated by tubular secretion.     

Pharmacokinetics, metabolism, and renal clearance of sulfadiazine, sulfamerazine, and sulfamethazine and of their N4-acetyl and hydroxy metabolites in calves and cows

The effect of molecular structure on the drug disposition and protein binding in plasma and milk, the urinary recovery, and the renal clearance of sulfadiazine, sulfamerazine, and sulfamethazine and of their N4-acetyl and hydroxy derivatives were studied in calves and cows. Sulfadiazine was highly acetylated and was slightly hydroxylated. Sulfamerazine and sulfamethazine were hydroxylated predominantly at the methyl group of the pyrimidine side chain; hydroxylation of the pyrimidine ring itself was more extensive for sulfamethazine than for sulfamerazine. At dosages between 100 and 200 mg/kg of body weight, sulfamethazine had a capacity-limited elimination pattern, which was not observed for sulfadiazine or sulfamerazine. The concentrations of the parent sulfonamide and its metabolites in plasma and milk were parallel, the latter being lower. Metabolite concentrations in milk were at least 8 times lower than those of the parent drug. Metabolism speeds drug elimination, producing compounds with renal clearance values higher than those of the parent drug. The effect on the metabolism and renal clearance of methyl substitution in the pyrimidine side chain is discussed.     

Age and dosage dependency in the plasma disposition and the renal clearance of sulfamethazine and its N4-acetyl and hydroxy metabolites in calves and cows

Plasma disposition, protein binding, urinary recovery, and renal clearance of sulfamethazine (SMZ), its N4-acetylsulfamethazine (N4-SMZ), and its 2 hydroxy metabolites--6-hydroxymethylsulfamethazine (SCH2OH) and 5-hydroxysulfamethazine (SOL)--and the glucuronide of the latter were studied in 7 cows and 7 calves to determine the relationship between these values and the age of the animal and dosage applied. A capacity-limited hydroxylation of SMZ into SCH2OH was observed in cows and calves given dosages of 100 to 200 mg/kg. A biphasic SMZ elimination curve and steady state in SCH2OH plasma concentration (6 to 15 micrograms/ml) were observed. The N4-SMZ plasma concentration-time curve was parallel to that of SMZ at the dosages and in all animals. The total body clearance and the cumulative urinary recovery (expressed as percentage of the dose) for SMZ and its metabolites depended on drug dosage and age of the animals. At dosages of SMZ less than 25 mg/kg, the main metabolite in the urine of calves and cows was SCH2OH (23% to 55.2%), whereas in calves given a larger dosage (100 mg/kg), the N4-SMZ and SOH percentages increased. The plasma protein binding of SMZ and its metabolites depended on the SMZ plasma concentration. Hydroxylation lowered the protein binding (from 75-80%) to 50%. The renal clearance of SMZ was dependent on urine flow in all animals. The renal clearance of the SCH2OH metabolite was 2 to 3 times greater than the creatinine clearance value; thus, this compound was excreted by glomerular filtration and partly by tubular secretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative aspects and sex differentiation of plasma sulfamethazine elimination and metabolite formation in rats, rabbits, dwarf goats, and cattle.

Plasma disposition and urinary recovery of sulfamethazine (SMZ), its N4-acetylated metabolite (N4AcSMZ), and 2 of its hydroxylated metabolites--5-hydroxysulfamethazine (5OHSMZ) and 6-hydroxymethylsulfamethazine (6CH2OHSMZ)--were determined in either sex of 4 animal species: rats, dwarf goats, rabbits, and cattle. Rats, rabbits, and dwarf goats had significant (P < 0.01) sex difference in SMZ plasma clearance. Male rats had higher plasma clearance than did female rats, and excreted higher amounts of the hydroxy metabolites and lower amounts of N4AcSMZ. The N4AcSMZ metabolite was predominant in plasma and urine of rabbits. Male rabbits had higher plasma clearance than did female rabbits, but differences in metabolite profile were not apparent. With regard to plasma SMZ elimination, the situation in goats was opposite to that in rats. Male goats had considerably lower clearance than did female goats. This was associated with a lower hydroxylation rat in males. Plasma half-life of SMZ in cows was lower than that in bulls, probably because of a smaller distribution volume in cows. Compared with elimination via urine, elimination via milk was negligible in cows. Significant differences in metabolite profiles were not found between bulls and cows. Similar to those in rats and mice, hormone-dependent xenobiotic metabolic pathways may exist in other species. Depending on species and xenobiotic compound residue concentrations of xenobiotics, their metabolites, or both may differ with sex of the animal, or may be altered after treatment with anabolic hormones.     

Pharmacokinetics, metabolism and renal clearance of sulphatroxazole in calves and cows

The pharmacokinetic analysis of plasma concentration--time curves after a single i.v. dose of 20 mg/kg sulphatroxazole (STZ) to calves and cows revealed a small distribution volume of STZ (mean VD(area) = 0.22-0.26 l/kg) and an age dependent elimination (mean t1/2 6.6-18.8 h). In calves and cows, STZ was extensively metabolized into the N4-acetyl and 5-hydroxy derivatives. In the plasma of calves, the N4-acetyl metabolite (N4-STZ) was present in greater amounts than the hydroxy metabolite (5-OH-STZ), while in cows' plasma concentration of these two metabolites were similar. In the milk of dairy cows STZ concentrations paralleled those of the metabolites and were approximately 21 times lower than corresponding plasma concentrations. The mean plasma protein binding of STZ and its metabolites ranged from 36.4 to 82.5% of total concentration. The N4-STZ derivative was excreted by tubular secretion; the 5-OH-STZ and the parent compound, mainly by glomerular filtration. In calves the majority of STZ administered was excreted as N4-STZ (40-52%), while in cows the parent drug dominated the urinary excretion (36%).     

Pharmacokinetics of a sulphamethoxazole/trimethoprim formulation in pigs after intravenous administration

Plasma disposition, metabolism, protein binding and renal clearance of sulphamethoxazole (SMZ) and trimethoprim (TMP) were studied in four pigs after intravenous administration at a dose of 40 and 8 mg/kg, respectively. SMZ and TMP were quickly eliminated (mean elimination half-lives: 2.7 and 2.4 h, respectively). SMZ was predominantly acetylated; no hydroxy and glucuronide derivates could be detected in plasma and urine. TMP was 0-demethylated into 4-hydroxytrimethoprim (M1) and 3-hydroxytrimethoprim (M4) metabolite and subsequently extensively glucuronidated. SMZ, TMP and its M1 metabolite were excreted predominantly by glomerular filtration, while N4-acetylsulphamethoxazole and glucuronide conjugates of the M1 and M4 metabolites of TMP were actively eliminated by tubular secretion. The proportional drug percentage being present in the urine as parent compound was 13.1% for TMP and 16.0% for SMZ. The glucuronide conjugates of the M1 and M4 metabolites formed the main part (81.5%) of urinary TMP excretion pattern.     

Pharmacokinetics of sulphamethoxazole in calves and cows

Summary

The kinetics of sulphamethoxazole (SMZ) in plasma and milk, and its metabolism, protein binding and renal clearance were studied in three newborn calves and two dairy cows after intravenous administration. SMZ was predominantly acetylated; no hydroxy and glucuronide derivatives could be detected in plasma and urine. Age‐dependent pharmacokinetics and metabolism of SMZ were observed. The plasma concentration‐time curves of the N₄‐acetyl metabolite in the elimination phase were parallel to those of the parent drug; the N₄‐acetyl metabolite plasma percentage depended on age and ranged between 100% (new‐born) to 24.5% (cow). SMZ was rapidly eliminated (elimination half‐lives: 2.0–4.7 h) and exhibited a relatively small distribution volume (V_Darea: 0.44–0.57 l/kg). SMZ was excreted predominantly by glomerular filtration, while its N₄‐acetyl metabolite was actively eliminated by tubular secretion.     

Pharmacokinetics of sulphanilamide and its three acetyl metabolites in dairy cows and calves

An intravenous low dosage of sulphanilamide (SAA) (14.0 mg/kg) to 6 pre-ruminant calves revealed a biphasic SAA plasma disposition with a mean elimination half-life of 4.1 h. The main metabolite in plasma was N4-acetylsulphanilamide (N4), which 4 hours after injection exceeded the parent SAA plasma concentration. Urinary recovery of SAA was 10 to 16% of the dose; of N4, it was at least 69%. Traces of the N1-acetyl (N1) metabolite and the doubly acetylated derivative (N1N4) were present in urine. The renal clearances of the N1 and N4 metabolites showed a tubular secretion pattern, which was at least 2 to 6 times higher than that of SAA. A single high oral SAA dose of 200 mg/kg to 3 dairy cows resulted in extensive metabolism of SAA into N4, N1, and N1N4 metabolites; their mean maximum plasma concentrations were 64, 48, 0.72 and 24 micrograms/ml, respectively. The mean disposition half-life of SAA in plasma and milk was 10 h. In milk the metabolite concentrations exceeded those in plasma; the N4 and N1N4 metabolite concentrations in milk exceeded that of SAA. The mean maximum concentrations of SAA, N4, N1, and N1N4 in milk were 52, 89, 2.3, and 98 micrograms/ml, respectively. For SAA and its metabolites, the binding to plasma and milk proteins was determined. No glucuronide or sulphate conjugates of SAA and its acetyl metabolites could be found in plasma, milk, or urine. Based on the sensitivity of the bioassay (0.2 micrograms SAA/ml), a withholding time of 5 days was suggested for milk following single oral SAA dosage of 200 mg/kg.     

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.     

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.     

Residues of sulphadimidine and its metabolites in eggs following oral sulphadimidine medication of hens

The depletion of sulphadimidine (SDM) and its N4-acetyl and hydroxy metabolites was studied in eggs laid by hens after administration of either a single or multiple oral dosages of 100 mg SDM/kg. During medication and until 1 day after the last dose, the SDM and its metabolite concentrations in the egg white exceeded those in the egg yolk and reflected the plasma levels. In the period starting 2 days after the (last) dosage, the SDM concentration in the yolk became higher than in the egg white, and the drug depletion curves ran parallel. The mean maximum amount of SDM found in the whole egg was 1500 micrograms after a single and 1280 micrograms after multiple dosage. In eggs, traces of the N4-acetyl and 6-methylhydroxy metabolites could be detected (mainly in the egg white), and their concentrations were approximately 40 times lower than those of the parent drug. A highly significant correlation (P less than 0.005) was found between the development stage of the oocyte at the time of (last) medication and the amount of SDM found in the egg that developed from it. A period of 7 or 8 days after the (last) dosage of 100 mg SDM/kg/day is required to obtain SDM levels below 0.1 micrograms/g egg.     

Fish and antibiotics: pharmacokinetics of sulphadimidine in carp (Cyprinus carpio)

Pharmacokinetics, metabolism and clearance of sulphadimidine (SDM) were studied after a single intraperitoneal injection of SDM in carp at 20 degrees C. SDM was acetylated and hydroxylated to a small extent. The main metabolite was N4-acetyl derivative amounting only 2% of the total drug dose excreted; hydroxylation was less important (0.41% of the dose). The elimination half-life for SDM in carp was 17.5 h. The clearance values for SDM and its metabolites were equivalent. The importance of pharmacokinetic studies in different fish species is discussed.     

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.     

The biotransformation of sulfadimethoxine, sulfadimidine, sulfamethoxazole, trimethoprim and aditoprim by primary cultures of pig hepatocytes

The in vitro biotransformation of three sulfonamides, trimethoprim and aditoprim, was studied using primary cultures of pig hepatocytes. Incubation of monolayer cultures with sulfadimethoxine (SDM), sulfamethoxazole (SMX) and ¹⁴C-sulfadimidine (SDD) resulted in the formation of the corresponding N 4-acetylsulfonamide to different extents, depending upon the molecular structure of the drug. Addition of the acetylsulfonamides to the cells showed that these compounds were deacetylated, each to a different extent. A relatively low degree of acetylation (in the case of SDD) was paralleled by extensive deacetylation (i.e. AcSDD), whereas extensive acetylation (i.e. SMX) was in concert with minor deacetylation (i.e. AcSMX). The addition of bovine serum albumin to the medium resulted in a decrease in conversion of sulfonamides as well as acetylsulfonamides. The main metabolic pathway of ¹⁴C-trimethoprim (TMP) was O -demethylation with subsequent conjugation. Two hydroxy (demethyl) metabolites were formed, namely 3'- and 4'-demethyl trimethoprim, which were both glucuronidated while 3'-demethyl trimethoprim was also conjugated with sulphate. The capacity to form conjugates with either glucuronic acid or sulphate was at least as high as the capacity for O -demethylation since more than 90% of the metabolites were excreted as conjugates in the urine of pigs. Addition of ¹⁴C-aditoprim (ADP) to the hepatocytes led to the N -demethylation of ADP to mono-methyl-ADP and di-desmethyl-ADP. During the incubation another three unknown ADP metabolites were formed. In contrast to TMP, no hydroxy metabolites or conjugated metabolites of aditoprim were formed. These in vitro results were in agreement with the in vivo biotransformation pattern of the studied sulfonamides and trimethoprim in pigs.     

Pharmacokinetics of sulfamethazine in male, female and castrated male swine

The concentration of sulfamethazine in plasma and sulfamethazine and its metabolites in urine were compared in male, female and castrated male swine. A surgical technique for placement of catheters in the urinary bladder was used to facilitate the collection of urine in males and castrated males. The elimination rate of sulfamethazine from plasma and the excretion of parent drug and metabolites into urine did not differ significantly among females, males and castrated male swine.     

The renal clearance of inulin, creatinine, trimethoprim and sulphadoxine in horses

The clearance of inulin and creatinine were almost identical in horses, indicating that creatinine clearance can be used for estimation of the glomerular filtration rate in horses. Trimethoprim (TMP) is excreted in urine by glomerular filtration, active tubular secretion and back-diffusion. The clearance of TMP is highly influenced by urine pH, but also by the plasma concentration of the drug and by the degree of diuresis. The results indicate self-depression of the active tubular secretion of TMP at plasma concentrations above 1–2 μg/ml. The renal excretion of sulphadoxine in horses involves glomerular filtration and a pronounced back-diffusion. The clearance of sulphadoxine is dependent on urine pH and increases with increasing pH. The clearance of N⁴-acetyl sulphadoxine was higher than the clearance of the parent compound. The renal excretion of N⁴-acetyl sulphadoxine was shown to involve glomerular filtration, active tubular secretion and back-diffusion.     

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 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.