<i>In vitro</i>antimicrobial activity of hydroxy and N<sub>4</sub>‐acetyl sulphonamide metabolites

Nouws, J. F. M.; Vree, T. B.

doi:10.1080/01652176.1985.9693956

Cited by 39 publications

(18 citation statements)

References 14 publications

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“…The concentrations of the N4-acetyl metabolite should therefore be rather low in plasma. The tested sulphonamides are mainly eliminated by metabolism in cattle and undergo both hydroxylation and acetylation (16,19,20,24). It seems that the N4-acetyl sulphonamides are deacetylated in cattle at a rate that is faster than the acetylation process (17,18).…”

Section: Sulphadimidine and Sulphamerazine Pharmacokineticsmentioning

confidence: 99%

“…As a consequence, the area under the plasma concentration-time curve of the unchanged sulphonamide should be lowered to about 30 %, and thus the volume of distribution and the clearance of both SDM and SMR should be increased to about 40 %. The hydroxy metabolites of SDM and SMR are microbiologically active exhibiting approximately 40 O/O of the activity of the parent drug (19). They therefore contribute also to the antimicrobial therapy and the calculated half-lives could be used to estimate the dosage interval.…”

Section: Sulphadimidine and Sulphamerazine Pharmacokineticsmentioning

confidence: 99%

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Pharmacokinetics of Aditoprim, a New Long‐acting Dihydrofolate Reductase Inhibitor, in Heifers

Jordan

Klatt²,

Ludwig

1987

Journal of Veterinary Medicine Series A

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The pharmacokinetics of aditoprim, a new dihydrofolate reductase (DHFR) inhibitor, and trimethoprim (TMP) were studied in heifers following a single intravenous injection of a 10rng/kg b. w. dose. Aditoprim had a larger volume of distribution at steady state (6.5 k 0.6 Pkg) than TMP (1.1 +_ 0.1 I/kg) and this probably reflects a better tissue penetration than TMP. Both antimicrobials had the same high plasma clearance (5.0 k 1 .O Urnin). Accordingly, aditoprim exhibited a longer halflife (4-6.711) than TMP which was 1.3h, as reported by several authors. Moreover, the plasma concentrations of the new antimicrobial were higher than those of TMP, starting from 4 hours after the drug was injected. For these reasons, the duration of the in vivo bacteriostatic activity of aditoprim should be significantly longer than that of TMP.Aditoprim was also injected intravenously into heifers in combination with either sulphadimidine (SDM) or sulphamerazine (SMR) in a 5:l w/w sulphonamide/aditoprim ratio. The dose was 15 mg of the combination/kg b. w. The pharmacokinetics of the two combinations showed no significant differences. The half-lives of SDM and SMR were both 4 hours, and the pharmacokinetic parameters of aditoprim did not differ significantly from those found when the drug was injected alone. Thus, the half-life of the new DHFR inhibitor appeared to be in the same range as that of the sulphonamides commonly used in veterinary medicine, while its antimicrobial activity was considerably higher. The use of aditoprim as a single drug could thus be envisaged as well as in combination with a sulphonamide.

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Section: Sulphadimidine and Sulphamerazine Pharmacokineticsmentioning

confidence: 99%

Section: Sulphadimidine and Sulphamerazine Pharmacokineticsmentioning

confidence: 99%

Pharmacokinetics of Aditoprim, a New Long‐acting Dihydrofolate Reductase Inhibitor, in Heifers

Jordan

Klatt²,

Ludwig

1987

Journal of Veterinary Medicine Series A

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“…Microbial inhibition tests lack sensitivity to the N4 sulphonamide metabolites (Nouws et al 1985) and usually provide next day test results. Applying an additional de-acetylation to urine or renal pelvis fluid samples can improve the sensitivity.…”

Section: Introductionmentioning

confidence: 99%

Application of an enzyme immunoassay for the determination of sulphamethazine (sulphadimidine) residues in swine urine and plasma and their use as predictors of the level in edible tissue

Haasnoot

Korsrud

Cazemier

et al. 1996

Food Additives and Contaminants

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The potential of an enzyme immunoassay (EIA) with high cross-reactivity towards the major metabolite (N4-acetyl-sulphamethazine) of sulphamethazine was tested for screening fluids and tissues. Healthy pigs were given 20 mg sulphamethazine per kg body weight per day in their drinking water for 2 days. Groups of four pigs were slaughtered after 3, 4 and 7 days withdrawal. The results were compared with liquid chromatographic analysis for urine, plasma, kidney, liver, gluteal muscle and diaphragm. In general, concentrations found by the EIA were higher than those found by liquid chromatography (LC) because sulphamethazine metabolites were detected by the EIA and not by LC. Using the EIA for the detection of sulphamethazine and the major metabolite in urine and plasma, predictive relationships (tissue-fluid ratios) for the concentration of the parent drug in tissue, determined by LC, were calculated. The tissue-plasma ratios for muscle, liver and kidney were 0.1, 0.2 and 0.1, respectively. The tissue-urine ratios for muscle, liver and kidney were 0.02, 0.03 and 0.03, respectively. Owing to the higher concentration of the parent drug in both fluids, the presence of the major metabolite in urine and the sensitivity of the EIA, tissue can be screened for low concentrations of sulphamethazine.

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“…The metabolites of interest should still have a similar structure as the parent drug and, therefore, retain to a greater or lesser extent their bioactive profile against micro-organisms. Earlier investigations about the biological activity of metabolites showed action of hydroxylated metabolites of sulfadiazine against different bacterial strains in contrast to N-acetyl sulfadiazine, which showed no antimicrobial activity [15][16][17]. In the latter case, however, biological activity could be regained after a possible cleavage of the N-acetyl group by microorganisms yielding the parent drug.…”

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confidence: 99%

Structural characterization of sulfadiazine metabolites using H/D exchange combined with various MS/MS experiments

Pfeifer¹,

Tuerk

Fuchs³

2005

J. Am. Soc. Mass Spectrom.

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Two major metabolites and one minor metabolite of sulfadiazine were found in pig manure, using a special combination of different MS techniques like parent and product ion scans, H/D exchange, accurate mass measurement, and MS/MS experiments with substructures. N4-acetylsulfadiazine and 4-hydroxysulfadiazine were identified as major metabolites. N4-acetylsulfadiazine could be verified by H/D exchange and comparison with product ion spectra of a synthetic reference compound. In the case of 4-hydroxysulfadiazine, the majority of possible isomers could be discounted after H/D exchange. Substructure-specific MS/MS experiments with fragment ions and comparison with product ion spectra of two references revealed the presence of 4-hydroxysulfadiazine. The minor metabolite was characterized to some degree using H/D exchange and tandem mass spectrometry in combination with a high-resolution time of flight mass spectrometer. The aminopyrimidine moiety contained an additional modification with a likely elemental composition of . Antibiotics and antimicrobial agents are used for both therapeutic and prophylactic purposes in addition to their application as growth promoters. The antimicrobial sulfonamides are one class of pharmaceuticals that is widely used. As a consequence, these compounds have been found in surface and ground water, liquid manure, and soil [3][4][5][6][7][8][9][10][11][12]. After administration to animals, the majority of the pharmaceuticals used are excreted unchanged or as phase I and phase II metabolites. As part of an environmental risk assessment, these metabolites also have to be characterized because phase I metabolites can still be active against bacteria and phase II metabolites can be converted back to the parent drug or phase I metabolites. Moreover, very little is known about the capacity of microbiological decay and the occurrence of new metabolites after incubation for several months in a manure tank.There are only a few references describing the metabolism of sulfadiazine in pigs [13,14]. After intravenous administration of 40 to 60 mg sulfadiazine per kg body weight to male pigs without coadministration of trimethoprim, only low levels of metabolites have been observed. The N-acetyl sulfadiazine was the main metabolite in plasma. Traces of 4-hydroxysulfadiazine were also detected. N-acetyl sulfadiazine and 4-hydroxysulfadiazine were the major metabolites in urine collected up to three hours after application. No further metabolites were identified and investigations in feces were not carried out.The aim of the present work was to use different mass spectrometric strategies to identify possible metabolites of the widely used drug sulfadiazine in manure originating from a pig farm. The metabolites of interest should still have a similar structure as the parent drug and, therefore, retain to a greater or lesser extent their bioactive profile against micro-organisms. Earlier investigations about the biological activity of metabolites showed action of hydroxylated metabolites of sulfadiazine ag...

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In vitroantimicrobial activity of hydroxy and N₄‐acetyl sulphonamide metabolites

Cited by 39 publications

References 14 publications

Pharmacokinetics of Aditoprim, a New Long‐acting Dihydrofolate Reductase Inhibitor, in Heifers

Pharmacokinetics of Aditoprim, a New Long‐acting Dihydrofolate Reductase Inhibitor, in Heifers

Application of an enzyme immunoassay for the determination of sulphamethazine (sulphadimidine) residues in swine urine and plasma and their use as predictors of the level in edible tissue

Structural characterization of sulfadiazine metabolites using H/D exchange combined with various MS/MS experiments

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In vitroantimicrobial activity of hydroxy and N4‐acetyl sulphonamide metabolites

Cited by 39 publications

References 14 publications

Pharmacokinetics of Aditoprim, a New Long‐acting Dihydrofolate Reductase Inhibitor, in Heifers

Pharmacokinetics of Aditoprim, a New Long‐acting Dihydrofolate Reductase Inhibitor, in Heifers

Application of an enzyme immunoassay for the determination of sulphamethazine (sulphadimidine) residues in swine urine and plasma and their use as predictors of the level in edible tissue

Structural characterization of sulfadiazine metabolites using H/D exchange combined with various MS/MS experiments

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In vitroantimicrobial activity of hydroxy and N₄‐acetyl sulphonamide metabolites