Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

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    The determination of biurea: a novel method to discriminate between nitrofurazone and azodicarbonamide use in food products
    Mulder, P.P.J. ; Beumer, B. ; Rhijn, J.A. van - \ 2007
    Analytica Chimica Acta 586 (2007)1-2. - ISSN 0003-2670 - p. 366 - 373.
    performance liquid-chromatography - mass-spectrometry - bound metabolites - semicarbazide - furazolidone - antibiotics - depletion - tissues - liver
    Recently doubts have arisen on the usefulness of semicarbazide as marker residue for the illegal use of the antibiotic nitrofurazone (NFZ) in aquaculture and poultry production. Most notably azodicarbonamide (ADC) has been implicated as an alternative source of semicarbazide. ADC is used in some countries as a dough conditioner at concentrations up to 45 mg kg¿1. The use of ADC-treated flour or dough in coated or breaded food products may generate false non-compliant results in the analytical method for nitrofurazone metabolites, which is currently in use. During the dough preparation process ADC is largely reduced to biurea, which can be considered as an appropriate marker residue of ADC. Thus far no methods have been published for the determination of biurea in food commodities. Due to its polar nature it is very difficult to generate sufficient retention on conventional C18 HPLC columns. With a TSK amide HILIC type column good retention was obtained. A straightforward extraction-dilution protocol was developed. Using a mixture of dimethyl formamide and water biurea was nearly quantitatively extracted from a variety of fresh, coated and processed products. Mass spectrometric detection was performed with positive electrospray ionisation. The sensitivity and selectivity of the mass spectrometer for biurea was very good, allowing detection at concentrations as low as 10 ¿g kg¿1. However, in some extracts severe ion suppression effects was observed. To overcome the implications of ion suppression on the quantitative performance of the method an isotopically-labelled biurea internal standard was synthesized and incorporated in the method. The method developed can be used effectively in nitrofurazone analysis to eliminate the risk of false non-compliant results due to the presence of azodicarbonamide-treated components in the food product.
    Nitrofuran antibiotic residues in pork The FoodBRAND retail survey
    O'Keeffe, M. ; Conneely, A. ; Cooper, K.M. ; Kennedy, D.G. ; Kovacsics, L. ; Fodor, A. ; Mulder, P.P.J. ; Rhijn, J.A. van; Trigueros, G. - \ 2004
    Analytica Chimica Acta 520 (2004)1-2. - ISSN 0003-2670 - p. 125 - 131.
    chromatography-mass-spectrometry - liquid-chromatography - furazolidone - tissues - 3-amino-2-oxazolidinone - furaltadone - metabolites - liver - pigs
    Use of nitrofuran drugs in food-producing animals has been prohibited within the EU because they may represent a public health risk. Monitoring compliance with the ban has focused on the detection of protein-bound nitrofuran metabolites which, in contrast to the parent compounds, are stable and persist in animal tissues. As part of the "FoodBRAND" project, an extensive survey of pork was undertaken across 15 European countries. Samples (n = 1500) purchased at retail outlets were analysed for the nitrofuran metabolites AOZ, AMOZ, AHD and SEM using LC-MS/MS determination of nitrobenzaldehyde derivatives. Limits of quantification for the method were 0.1 g/kg (AOZ, AMOZ), 0.2 g/kg (SEM) and 0.5 g/kg (AHD). Of the 1500 samples tested, measurable residues of nitrofuran metabolites were confirmed in 12 samples (0.8% incidence overall) of which 10 samples were purchased in Portugal (AOZ, 0.3 g/kg; AMOZ, 0.2¿0.6 g/kg) and one sample each in Italy (AMOZ, 1.0 g/kg) and Greece (AOZ, 3.0 g/kg)
    Adducten van nitrofuranen: metabolisme, uitscheidingskinetiek en analytiek
    Zuidema, T. - \ 2003
    Wageningen : RIKILT (Rapport / RIKILT 2003.022) - 56
    nitrofuranen - derivaten - vleeskuikens - blootstelling - metabolisme - furazolidon - in vitro - heterocyclische verbindingen - analytische scheikunde - nitrofurans - derivatives - broilers - exposure - metabolism - furazolidone - in vitro - heterocyclic compounds - analytical chemistry
    Absorption of a mutagenic metabolite released from protein-bound residues of furazolidone
    Hoogenboom, L.A.P. ; Bruchem, G.D. van; Sonne, K. ; Enninga, I.C. ; Rhijn, J.A. van; Heskamp, H. ; Huveneers-Oorsprong, M.B.M. ; Hoeven, J.C.M. van der; Kuiper, H.A. - \ 2002
    Environmental Toxicology and Pharmacology 11 (2002). - ISSN 1382-6689 - p. 273 - 287.
    furazolidone - bound residues - nitrofurans - MAO-inhibition
    The use of nitrofurans as veterinary drugs has been banned in the EU since 1993 due to doubts on the safety of the protein-bound residues of these drugs in edible products. Following treatment of pigs with the veterinary drug furazolidone free 3-amino-2-oxazolidinone (AOZ), the side-chain of the drug, could be detected in the blood in concentrations up to 0.3 g/ml. The identity of the free AOZ was confirmed by LC/MS. This shows that the side-chain can be released from the parent drug, most likely under the acidic conditions in the stomach. Free AOZ was also detected in the blood of rats fed pig liver with protein-bound residues of furazolidone. Incubation of isolated pig hepatocytes with radiolabeled AOZ, resulted in the formation of protein-bound metabolites, to a similar extent as observed with furazolidone itself. Much lower levels were formed in the presence of dimethylsulfoxide or 4-chlorobenzenesulfonamide, most likely due to inhibition of the enzyme involved in the metabolic activation of AOZ. These compounds also prevented the inhibition by AOZ of monoamine-oxidase (MAO) activity in pig hepatocytes. These data strongly indicate that the protein-bound metabolites of furazolidone in tissues of treated animals are derived following metabolic activation of furazolidone itself, but also of the free AOZ side-chain, following its release from the parent drug. In addition to the MAO-inhibition and formation of protein-adducts, AOZ gave a dose-related positive respons in the Salmonella/microsome mutagenicity test especially in the presence of rat liver S9-mix, in tester strains TA 1535 and TA 100. Furthermore, a positive response was obtained in the chromosome aberration test with human lymphocytes and in the bone marrow micronucleus test with mice treated intraperitoneally with AOZ. It is concluded that ingestion of protein-bound residues of furazolidone results in the release and absorption of AOZ, a compound with potential mutagenic properties. This is the first report showing that protein-bound residues of veterinary drugs can be of toxicological significance.
    In vitro toxicological studies and real time analysis of residues in food : reports of exchange visits 1993/1994
    Kuiper, H.A. - \ 1996
    Wageningen : RIKILT-DLO - ISBN 9789056010126 - 126
    analytische methoden - in vitro - experimenten - aldicarb - oxfendazol - furazolidon - elisa - clenbuterol - analytical methods - in vitro - experiments - aldicarb - oxfendazole - furazolidone - elisa - clenbuterol
    In vitro toxicological studies and real time analysis of residues in food : proceedings of the workshops held in Ghent, May 22-24, 1992 and Thessaloniki, October 30-31, 1992
    Kuiper, H.A. ; Hoogenboom, L.A.P. - \ 1992
    Wageningen : RIKILT-DLO - ISBN 9789056010034 - 176
    food analysis - in vitro - experiments - liver cells - levamisole - furazolidone - beta-adrenergic agonists - xenobiotics - voedselanalyse - in vitro - experimenten - levercellen - levamisol - furazolidon - bèta-adrenerge agonisten - xenobiotica
    In vitro toxicological studies and real time analysis in food : proceedings of the workshops held in Berlin, March 8-9, 1991, and Swansea, March 21-22, 1991
    Hoogenboom, L.A.P. ; Broex, N.J.G. - \ 1991
    Wageningen : RIKILT-DLO - ISBN 9789056010027 - 70
    food analysis - in vitro - experiments - perfusion - aldicarb - furazolidone - anthelmintics - liver cells - microsomes - voedselanalyse - in vitro - experimenten - perfusie - aldicarb - furazolidon - anthelmintica - levercellen - microsomen
    In vivo and in vitro metabolic studies of furazolidone
    Vroomen, L.H.M. - \ 1987
    Agricultural University. Promotor(en): J.H. Koeman, co-promotor(en): H.A. Kuiper. - S.l. : Vroomen - 155
    dierlijke producten - voedselbesmetting - furazolidon - varkensvlees - varkens - placebo's - vitaminen - animal products - food contamination - furazolidone - pigmeat - pigs - placebos - vitamins
    The experiments described in this thesis were undertaken to get a better understanding of the kinetics and biotransformation of
    the nitrofuran furazolidone upon oral administration to swine. Such information forms an essential prerequisite for making an
    appropriate assessment of the consumer hazards of edible products originating from animals treated with this compound. The experiments were conducted according to two different approaches:
    - kinetic studies in the target animal to determine the elimination kinetics of furazolidone and its metabolites from plasma and
    tissues upon oral administration of furazolidone
    - in vitro biotransformation studies using swine and rat liver microsomes to elucidate biotransformation routes and to identify
    reactive intermediates responsible for the interaction with biological macromolecules.

    Part I of this thesis starts with a description of some developments in animal husbandry during the last decades. This is followed by a review of literature data on physical/chemical and antimicrobial characteristics, toxicity, elimination kinetics and biotransformation of furazolidone (chapter 1).

    Part II of this thesis deals with the present study. In chapter 2 a fast, sensitive method has been described for the determination of furazolidone in swine plasma, muscle, liver, kidney, fat and urine based on high-performance liquid chromatographic separation after solid-phase extraction on Extrelut R1. The sensitivity of the method was 1-2 ng/ml (g) for plasma and tissues and 25 ng/ml for urine.

    From the kinetic studies the conclusion can be drawn that no accumulation of furazolidone occurs in blood after oral administration of furazolidone to both piglets (chapter 3) and adult swine (chapter 4); the half life time was respectively 45 and 60 minutes. Furazolidone was rapidly and almost completely metabolized and urine proved to be the major excretion pathway of formed metabolites: 61% of the radioactive dose administered to piglets had been exreted via the urine and 18% via faeces, while in urine of adult swine only traces of total dosed furazolidone could be recovered. In tissues of piglets and adult swine no residues of furazolidone could be detected at all. However, the experiments with piglets showed that relatively high levels of radioactivity were present in all tissues studied. After a withdrawal period of 14 days the concentrations varied from 0.9-4.3 pg-equivalents per gram tissue. Up to 56% of the radioactivity detected in organs and tissues appeared to be non-extractable and was partly associated with DNA. This may either be indicative for endogenous incorporation in physiologically occurring compounds or for covalent binding of reactive intermediate metabolites of furazolidone to biological macromolecules (chapter 3).

    Studies with the adult swine further revealed the formation of a cyano-derivative from furazolidone, namely 3-(4-cyano-2- oxobutylidene amino)-2-oxazolidone. In studies in other animal species, it was claimed that this cyano-derivative was a major metabolite in urine. However, this compound proved to be a minor metabolite in plasma (half life time: 4 hours) and tissues of adult swine. This may be explained by species differences in biotransformation of furazolidone, by a very fast elimination of the cyano-derivative via urine or by an effective trapping of reactive intermediate metabolites of furazolidone
    by biological macromolecules or agents like glutathione (chapter 4).

    Two major ethyl acetate extractable metabolites of furazolidone could be observed upon incubation in rat liver microsomes: the cyano-derivative referred to before and a reaction product of furazolidone with its open-chain acrylonitrile derivative, namely 2,3-dihydro-3cyanomethyl-2-hydroxy-5-nitro-lα,2-di-(2-oxo-oxazolidin-3-yl)iminomethylfuro[2,3-b]furan. Approximately 2-7% of the totally formed metabolites proved to be covalently bound to microsomal protein. This covalent binding could be inhibited by addition of glutathione, which also resulted in an almost complete shift from non-polar to watersoluble metabolites. No binding to DNA was detected when calf thymus DNA was added to a microsomal incubation mixture with furazolidone in contrast to the in vivo DNA interaction observed in the piglets. This may be explained by differences between the in vitro and in vivo situation in the availability of reactive intermediate metabolites of furazolidone for reaction with DNA (chapter 5).

    The above mentioned ethyl acetate extractable metabolites of furazolidone proved to be only minor conversion products of furazolidone upon incubation in swine liver microsomes, while the percentage of the protein bound metabolites formed was much higher, namely 12-22%. The site of attack on microsomal protein is probably formed by the thiol-group of cysteine as indicated by results of experiments performed with amino acids. Using mercapto-ethanol as a trapping agent for reactive intermediates, a new metabolite could be isolated upon incubation of furazolidone in swine liver microsomes. This compound was identified as a conjugation product of the open-chain acrylonitrile derivative of furazolidone with mercapto-ethanol, namely 3-(4-cyano-3-β-hydroxyethyl-mercapto2-oxobutylidene amino)-2-oxazolidone. This conjugate accounted for approximately 50% of total amount of metabolites formed. In addition, neither the above mentioned ethyl acetate extractable metabolites nor covalent binding to microsomal protein could be observed when mercaptoethanol was added to the incubation mixture, indicating that the openchain acrylonitrile derivative plays a central role in reductive biotransformation of furazolidone by swine liver microsomes (chapter 6).

    The open-chain acrylonitrile derivative of furazolidone binds reversibly with thiolgroup containing agents such as glutathione and mercapto-ethanol or with microsomal protein. The reversibility of the exchange reaction is dependent on pH as is demonstrated for the mercapto-ethanol conjugate. Below pH 2 this conjugate is stable; optimal exchange to microsomal protein is found between pH 7 and 10. The mercapto-ethanol conjugate gives a distinct direct positive response in the Salmonella/microsome test using tester strain TA 100. This is probably due to an interaction of the acrylonitrile moiety with DNA (chapter 7).

    It can be concluded that furazolidone is rapidly and almost completely metabolized upon oral administration to piglets. A major part of the formed metabolites proved to be non-extractable from the tissues. It can not be excluded that these non-extractable metabolites are the result of covalent binding of a reactive intermediate metabolite of furazolidone to biological macromolecules such as protein or DNA. From in vitro studies using swine liver microsomes evidence has been obtained showing that the open-chain acrylonitrile derivative plays a central role in the biotransformation of furazolidone.
    It has been shown that this reactive intermediate can bind reversibly to microsomal protein. Whether this non-enzymatic reaction also occurs in vivo is not yet known. As the possible presence of such covalently bound residues in edible tissues could have serious consequences for the acceptibility of the drug for massmedication of food producing animals, the identity of the non-extractable radioactive material in tissue of piglets should be further investigated, together with its bioavailability and toxicity. Efforts should also be made to identify the extractable radioactivity in tissues of piglets as only a small part of this fraction as so far has been identified.

    Bepaling van furazolidon in eieren
    Aerts, M.M.L. ; Beek, W.M.J. - \ 1984
    Wageningen : RIKILT (Verslag / RIKILT 84.49) - 4
    eieren - furazolidon - medicinaal voer - eggs - furazolidone - medicated feeds
    De eieren werden geanalyseerd met behulp van een intern analysevoorschrift en de positieve monsters werden ook geanalyseerd met behulp van een "diode array" detektor.
    Bepaling van furazolidon in eieren
    Beek, W.M.J. ; Buizer, F.G. - \ 1984
    Wageningen : RIKILT (Verslag / RIKILT 84.24) - 5
    eieren - furazolidon - hplc - eggs - furazolidone - hplc
    Er is een bepalingsmethode onttolikkeld voor de bepaling van furazolidon in eieren met behulp van hogedrukvloeistofchromatografie. Met behulp van "diode-array" detectie is ook getracht confirmatie van het gezochte residu uit te voeren.
    Furazolidone - resistente bacterien
    Anonymous, - \ 1971
    Wageningen : [s.n.] (Literatuurlijst / Centrum voor landbouwpublikaties en landbouwdocumentatie no. 3285)
    bibliografieën - immunologie - furazolidon - geneesmiddelresistentie - bacteriën - bibliographies - immunology - furazolidone - drug resistance - bacteria
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