Novel oxidative pathways of sulphapyridine and sulphadiazine by the turtle<i>Pseudemys scripta elegans</i>

Vree, T. B.; Vree, Jeroen B.; Kolmer, E. W. J. Beneken

doi:10.1080/01652176.1991.9694311

Cited by 7 publications

(7 citation statements)

References 21 publications

(27 reference statements)

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“…This may mean that the oxidative power of the pig for sulphapyridine is less than in man. Sulphadiazine is predominantly Nracetylated in man and pig, while pigs also show hydroxylation pathways leading to 4-hydroxysulphadiazine (4) and 4,6-dihydroxysulphadiazine, a metabolite also found in turtles (15). The male pigs studied by Nouws et al excreted more parent drug and N4-acetylsulphadiazine than the young female pig used in this study (4).…”

Section: Discussionmentioning

confidence: 63%

Comparison of the metabolism of four sulphonamides between humans and pigs

Vree

Kolmer

Peeters

1991

Veterinary Quarterly

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SUMMARY. Pigs are unable to form Ni-glucuronides of sulphadimethoxine and sulphamethomidine, while humans are able to do so. Pigs and humans are able to oxidise sulphapyridine and form the 0-glucuronide. The double conjugate N4-acetylsulphapyridine-0-glucuronide is formed in humans but not in pigs. Sulphadiazine is mainly acetylated in both humans and pigs. A hypothesis about Ni-glucuronidation is presented.

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Section: Discussionmentioning

confidence: 63%

Comparison of the metabolism of four sulphonamides between humans and pigs

Vree

Kolmer

Peeters

1991

Veterinary Quarterly

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“…Vree and co workers isolated the metabolite from the urine of dogs [5] and excreta of fresh water turtles Pseudemys scripta elegans by preparative TLC [8]. Dog's urine is relatively easy to analyse, because dogs are unable to acetylate sulfon amides [5].…”

Section: Discussionmentioning

confidence: 99%

“…Dog's urine is relatively easy to analyse, because dogs are unable to acetylate sulfon amides [5]. Excreta of turtles diluted in tank water give clean chromatograms containing 4-and 5-hydroxysulfadiazine [8]. Other reported conjugates of sulfadiazine included the deaminated metabolites [9].…”

Section: Discussionmentioning

confidence: 99%

Isolation, identification and determination of sulfadiazine and its hydroxy metabolites and conjugates from man and Rhesus monkey by high-performance liquid chromatography

Vree

Ven

Wissen

et al. 1995

Journal of Chromatography B: Biomedical Sciences and Applicatio

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A bstractThe following metabolites of sulfadiazine (S) were isolated from monkey urine by preparative HPLC: 5-hydroxysulfadiazine (50H), 4-hydroxysulfadiazine (40H) and the glucuronide (SOHgluc) and sulfate conjugate of 50H (50Hsulf). The compounds were identified by NMR, mass and infrared spectrometry and hydrolysis by /3-glucuronidase. The analysis of S, the hydroxymetabolites (40H, 50H) and conjugates N4-acetylsulfadiazine (N4), SOHgluc and 50Hsulf in human and monkey plasma and urine samples was performed using reversed-phase gradient HPLC with UV detection. In plasma, S and N4 could be detected in high concentrations, whereas the other metabolites were present in only minute concentrations. In urine, S, the metabolites and conjugates were present. The limit of quantification of the compounds in plasma varies between 0.2 and 0.6 /¿g/ml (S 0.31, N4 0.40, 40H 0.20, 50H 0.37, SOHgluc 0.33 and SOHsulf 0.57 ¿tg/ml). In urine it varies between 0.6 and 1.1 /¿g/ml (S 0.75, N4 0.80, 40H 0.60, 50H 0.80, SOHgluc 0.80 and SOHsulf 1.1 ¿¿g/ml). The method was applied to studies with healthy human subjects and Rhesus monkeys. The metabolites 5OH, SOHgluc and 50Hsulf were present in Rhesus monkey and not in man. Preliminary results of studies of metabolism and pharmacokinetics in Rhesus monkey and man are presented. Subject and monkeysA single oral dose of 500 mg S was adminis tered to one healthy human subject (male, 35 years old, 85 kg, slow acetylator of sulfonamides) with 100 ml of tap water after an overnight fast. The study had the approval of the hospital ethics committee and informed consent was obtained from the volunteer.Rhesus monkeys were obtained from the Cen tral Animal Laboratory, University of Nijmegen and the Laboratory Animals Breeding Ex perimental Farm of Shunde Guangdong (Beijing, China). One Rhesus monkey (female, 5 years old and weighing about 5 kg) was housed in a metabolic cage and fed orally with 50 mg/kg of sulfadiazine and serial plasma and urine samples were collected for 2 days. Three Rhesus monkeys (female, 4-5 years old and weighing about 5 kg) obtained from the Central Animal Laboratory, University of Nijmegen, were housed in a meta bolic cage and fed orally for 5 days with 50 mg/kg of sulfadiazine and all urine was collected for 6 days. The study had the approval of the ethics committee of the Animal Laboratory. SamplingBlood samples of 2 ml were drawn from the volunteer and collected in heparinized Eppendorf vials (2 ml) at regular time intervals during 2 days after administration by means of fingertip puncture with Monolet lancets (Monoject, St. Louis, MO, USA). After centrifuging at 3000 g for 5 min, plasma samples were stored at -20°C pending analysis.Urine was collected from untimed voiding. The total time of sample collection was 96 h. Three samples of 7 ml of each void were stored at -20°C pending analysis.Blood samples of 2 ml were drawn from the monkey by puncture of the vena mediana and collected in heparinized Eppendorf vials at 0.1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24 and 48 h ...

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“…The extent of hydroxylation depends on the type of species, age, and dose (11,12,(17)(18)(19). The presence of antimicrobially active metabolites may have consequences for the efficacy of treatment when these metabolites are present in high concentrations or when effective concentrations in plasma are reached.…”

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“…This method, however, cannot discriminate between different hydroxylated metabolites of sulfadiazine. By using highperformance liquid chromatography (HPLC), a variety of hydroxy metabolites of sulfadiazine have been discovered in different animal species (11,12,19). Recently, HPLC determination of sulfadiazine in the plasma and the urine of rhesus monkeys revealed the presence of five metabolites of sulfadiazine: N4-acetyl-sulfadiazine (N4-acetyl), 4-OH-sulfadiazine (4-OH), 5-OH-sulfadiazine (5-OH), 5-OH-glucuronide-sulfadiazine (5-OH-Gluc), and 5-OH-sulfate-sulfadiazine (5-OHSulf), (16a).…”

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confidence: 99%

In vitro effects of sulfadiazine and its metabolites alone and in combination with pyrimethamine on Toxoplasma gondii

Ven¹,

Vree²,

Melchers³

et al. 1995

Antimicrob Agents Chemother

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Sulfadiazine and the metabolites N4-acetyl-sulfadiazine, 4-OH-sulfadiazine, 5-OH-sulfadiazine, 5-OH-glucuronide-sulfadiazine, and 5-OH-sulfate-sulfadiazine were tested separately and in combination with pyrimethamine for the inhibitory activity on Toxoplasma gondii growth in vitro. Except for N4-acetyl-sulfadiazine, all sulfa compounds possessed anti-Toxoplasma activity. The addition of 0.05 g of pyrimethamine per ml, a concentration which in itself is not inhibitory, potentiated the microbial activity of sulfadiazine and its metabolites 100 fold.The combination of sulfadiazine and pyrimethamine is frequently used for the treatment of Toxoplasma gondii infections (9,14). Both drugs act synergistically in the metabolic pathway of folic acid, which in turn is required for the biosynthesis of purines, pyrimidines and certain amino acids (4).Studies on the antimicrobial activity of sulfadiazine metabolites are scarce. Pharmacokinetic studies of sulfadiazine so far have been performed by the method of Bratton and Marshall (1). This method, however, cannot discriminate between different hydroxylated metabolites of sulfadiazine. By using highperformance liquid chromatography (HPLC), a variety of hydroxy metabolites of sulfadiazine have been discovered in different animal species (11,12,19). Recently, HPLC determination of sulfadiazine in the plasma and the urine of rhesus monkeys revealed the presence of five metabolites of sulfadiazine: N4-acetyl-sulfadiazine (N4-acetyl), 4-OH-sulfadiazine (4-OH), 5-OH-sulfadiazine (5-OH), 5-OH-glucuronide-sulfadiazine (5-OH-Gluc), and 5-OH-sulfate-sulfadiazine (5-OHSulf), (16a). It was thought previously that rhesus monkeys and humans were similar in their metabolization of sulfadiazine (10). However, the three 5-OH metabolites have not been found in humans.A previous study with rhesus monkeys on the efficacy of pyrimethamine and sulfadiazine for the treatment of congenital T. gondii infection (15) raised the question of whether the metabolites of sulfadiazine possess antiparasitic activity. Nouws et al. (13) demonstrated that a hydroxylated metabolite of sulfadiazine had antimicrobial activity against Escherichia coli at 2.5% of the activity of the parental drug. N4-acetyl, on the other hand, showed no antimicrobial activity against this bacterium.In the present study the anti-Toxoplasma activities of sulfadiazine and the metabolites that have been found in rhesus monkeys were investigated in vitro. The activities of these drugs were also studied in combination with pyrimethamine.Anti-Toxoplasma activity was measured by quantitation of parasite growth using an enzyme-linked immunosorbent assay, which was performed directly on T. gondii-infected HEp-2 cells. The in vitro tests were performed as described previously by Derouin and Chastang (3). HEp-2 cells were prepared in 96-well tissue culture plates (Costar, Cambridge, Mass.) and grown to confluence. At the start of the assay, T. gondii parasites of the RH strain were transferred to fresh culture medium at a concentration of 10 5 ...

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Novel oxidative pathways of sulphapyridine and sulphadiazine by the turtlePseudemys scripta elegans

Cited by 7 publications

References 21 publications

Comparison of the metabolism of four sulphonamides between humans and pigs

Comparison of the metabolism of four sulphonamides between humans and pigs

Isolation, identification and determination of sulfadiazine and its hydroxy metabolites and conjugates from man and Rhesus monkey by high-performance liquid chromatography

In vitro effects of sulfadiazine and its metabolites alone and in combination with pyrimethamine on Toxoplasma gondii

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