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WO2008115580A2 - Procédé pour détecter le nitrofurane - Google Patents

Procédé pour détecter le nitrofurane Download PDF

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Publication number
WO2008115580A2
WO2008115580A2 PCT/US2008/003750 US2008003750W WO2008115580A2 WO 2008115580 A2 WO2008115580 A2 WO 2008115580A2 US 2008003750 W US2008003750 W US 2008003750W WO 2008115580 A2 WO2008115580 A2 WO 2008115580A2
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WO
WIPO (PCT)
Prior art keywords
nitrofuran
hydrolyzing
nitrobenzaldehyde
sample
metabolite
Prior art date
Application number
PCT/US2008/003750
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English (en)
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WO2008115580A3 (fr
Inventor
Say-Jong Law
Original Assignee
Charm Sciences, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Charm Sciences, Inc. filed Critical Charm Sciences, Inc.
Publication of WO2008115580A2 publication Critical patent/WO2008115580A2/fr
Publication of WO2008115580A3 publication Critical patent/WO2008115580A3/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
    • G01N33/9446—Antibacterials

Definitions

  • Nitrofurans are synthetic broad-spectrum antibiotics used in animal, aquaculture and honey production. Nitrofurans are antibacterial, antiprotozoan and growth promoters. In animal studies the parent drugs and their metabolites showed carcinogenic and mutagenic characteristics. For that reason, nitrofuran use in the treatment of animals used for food production is prohibited. Despite such bans, residues continue to appear in the food supply. In particular, metabolites of nitrofurans can be tissue or protein bound resulting in residue remaining long after administration of the parent drug.
  • the structures are as follows:
  • Nitrofurans are rapidly metabolized.
  • the in situ half-life can be less than two hours.
  • the nitrofuran parent may be reduced, such as by one or more nitroreductases.
  • the basic nitrofuranyl moiety (the common portion attached to the R group), is transformed into a different chemical group, while the R group (on the right hand side of the nitrofuran parent structure) remains intact.
  • Several methods for determining the use of a nitrofuran parent drug are via indirect metabolite detection.
  • Such methods include liquid chromatography with ultra violet detection (LC-UV), liquid chromatography with mass spectrometer detection (LC-MS), liquid chromatography with tandem mass spectrometer detection (LC -MS/MS) and immunodiagnostics.
  • the metabolite can be protein bound and, therefore, a hydrolysis step is used to cleave the side chain. Those hydrolysis and derivatization reactions often require 16- 24 hours prior to sample detection.
  • An aspect is a method and test kit that includes a sample preparation step that allows rapid results - less than 16 hours - when testing for nitrofuran in biological samples.
  • Sample preparation time can be reduced by decreasing the time for acid hydrolysis by one or a combination of: providing a concentration of NBA, or other aryl aldehyde with electron withdrawing group, effective to reduce time for acid hydrolysis to less than 16 hours; increasing incubation temperature to a level effective to reduce time for acid hydrolysis to less than 16 hours (for example above 37 degrees C, such as about 80 degrees C); and increasing amount or strength of acid used to a level effective to reduce time for acid hydrolysis to less than 16 hours.
  • An aspect includes reacting substituted or non-substituted 2-nitrobenzaldehyde (2- NBA) with the sample. Yet another aspect includes reacting substituted or non-substituted 4- nitrobenzaldehyde (4-NBA) with the sample. The resulting material is then tested for the presence of nitrofuran such as in an immunoassay or by any of a variety of liquid chromatography detection methods.
  • aspects include subjecting the sample to a rapid acid hydrolysis by reacting more than 10 millimolar (mM), for example 40 mM, of either 2-nitrobenzaldehyde (2-NBA) or 4-NBA (2-NBA and 4-NBA hereinafter referred to as NBA) with the sample in the presence of an acid, such as HCl. Concentration of acid can be approximately about 0.5 N' to about 2 N HCl.
  • aspects also include incubating the NBA/acid combination which can shorten the reaction time and maximize the yield of the product. Incubation temperature ranges include about 37 degrees C to about 100 degrees C. At above 37 degrees C, such as 50 degrees C, the sample can be ready for analysis in as little as about 2 hours.
  • the sample can be ready in as quickly as 15 minutes.
  • 2- NBA and 4-NBA it will be appreciated that other NBA isomers may be useful and other aryl aldehydes with electron withdrawing groups can be useful.
  • Embodiments include generating a 4-NP derivative of a nitrofuran.
  • Other embodiments include generating a 2-NP derivative of a nitrofuran (4-NP derivative and 2-NP derivative hereinafter referred to as NP derivative).
  • Yet other embodiments include generating a substituted or non-substituted NP derivative of a nitrofuran.
  • the NP derivative can be used for detecting a nitrofuran in a sample, such as a food sample.
  • proteinaceous samples such proteinaceous samples in which the nitrofuran is present as a biomolecule nitrofuran metabolite, may require the sample to be hydrolyzed, such as by acid hydrolysis.
  • the biomolecule could be a small molecular biochemical alone or conjugated further to a protein carrier, a peptide conjugated to a protein carrier, a protein, a nucleic acid, or a polysaccharide.
  • the acid hydrolysis can improve detection in an immunoassay, or liquid chromatography, particularly when the sample contains protein and/or the nitrofuran is present as a protein bound metabolite.
  • Higher concentrations of NBA greater than 1OmM, for example between 1OmM and 5OmM, such as about 40 mM, can help drive the acid hydrolysis at a faster rate.
  • Other factors that can allow faster acid hydrolysis include increased incubation temperature and increased volume, strength and/or concentration of acid.
  • the following diagrams illustrate the preparation of the 4-NP derivative of each of furazolidone (FZD), nitrofurantoin (NFT) and furaltadone (FTD).
  • FZD furazolidone
  • NFT nitrofurantoin
  • FTD furaltadone
  • the acid hydrolysis with 4-NBA causes the various R 2 groups on the nitrofuran or nitrofuran metabolite, whether parent, metabolite or protein bound metabolite, to be replaced by the 4- NBA with the resulting product being the 4-NP derivative.
  • the 4-NP derivative can be detected in the sample such as by using an immunoassay or liquid chromatography detection (e.g. UV, MS, MS/MS) with sensitivity to one or more of the 4-NP derivatives.
  • Furazolidone (FZD) Furazolidone metabolite (FZDM)
  • NFT nitrofurantoin
  • NFTM nitrofurantoin metabolites
  • Nitrofurantoin NFT
  • Nitrofurantoin metabolite NFTM
  • Furaltadone Furaltadone metabolite (FTDM)
  • ELISA formats include adsorbing antibody to an inert surface, for example a 96-well polystyrene plate. After adsorption of the antibody, the surface is washed with a solution of an appropriate blocking agent, for example casein from non-fat dry milk powder. After sample preparation such as acid hydrolysis with NBA, sample can be added to the well. A nitrofuran tracer is also added to the plate. The tracer can be either nitrofuran metabolite or nitrofuran derivative directly labeled with an enzyme or indirectly, for example utilizing a biotin/avidin bridge.
  • Analyte in the sample competes with tracer to bind to the immobilized (or coated) antibody. After washing, the surface is treated with a substrate that forms a colored product when contacted with the bound enzyme tracer. Color intensity is inversely related to the amount of analyte present. ⁇ ⁇ [. ⁇ ⁇ .
  • an analyte competitor such as S-linked nitrofuran metabolite-Cys-BSA or N-linked nitrofuran metabolite-BSA
  • Enzyme labeled antibody is then mixed with the previously prepared sample (for example by the acid hydrolysis with NBA) and applied earlier or simultaneously to the plate. Uncaptured labeled antibody is then washed off the surface. After substrate is added the color development is observed. In this example, there is an inverse relationship between the color intensity and the amount of antigen present.
  • antibody can bind to the NP derivative in the sample preparation to form a complex.
  • the method and device can utilize a membrane strip, such as a nitrocellulose strip.
  • a membrane strip such as a nitrocellulose strip.
  • One example utilizes colloidal gold particles as a label bound to the antibody.
  • the size of the particle can be adapted to the porosity of the membrane strip.
  • the particles are preferably sufficiently small to be transported along the membrane by capillary action of a fluid sample.
  • the number of particles present in the test strip may vary, depending on the size and composition of the test strip and the desired level of sensitivity of the assay. For example, using fewer particles may help increase test sensitivity.
  • any one of a variety of labels may be employed including colloidal gold particles.
  • Other useful labels include, but are not limited to, colloidal sulphur particles; colloidal selenium particles; colloidal barium sulfate particles; colloidal iron sulfate particles; metal iodate particles; silver halide particles; silica particles; colloidal metal (hydrous) oxide particles; colloidal metal sulfide particles; colloidal lead selenide particles; colloidal cadmium selenide particles; colloidal metal phosphate particles, colloidal metal ferrite particles, any of the above-mentioned colloidal particles coated with an organic or inorganic layer; protein or peptide molecules; liposomes; or organic polymer latex particles, such as polystyrene latex beads.
  • Still other labels may also be used including, but not limited to, luminescent labels; fluorescent labels; or chemical labels, such as electroactive agents (e.g., ferrocyanide); enzymes; radioactive labels; or radiofrequency labels.
  • the test device can include a support strip and a sample-absorbing matrix, for example composed of a cellulosic, sponge-like material. Such a sample-absorbing matrix allows for absorbing an amount of the sample and can also filter unwanted substances from the sample prior to the sample contacting test reagents.
  • the test device also can include a mobile-phase support attached to the support strip and in contact with the sample-absorbing matrix.
  • a mobile-phase composition is disposed within or on the mobile-phase support and has one or more labeled receptors, such as one or more gold labeled antibodies with affinity to a nitrofuran and/or metabolite thereof.
  • kits may also include various combinations of polyclonal and monoclonal antibodies.
  • the mobile-phase composition can be applied prior to test operation, for example by spraying and drying onto a porous surface such as polyethylene membrane.
  • a useful membrane is POREX® (POREX is a registered trademark of Porex Technologies Corp. of Fairburn, Georgia) membrane.
  • the mobile-phase composition can be carried in the sample flow together with the sample.
  • the sample flows and the antibody binds to nitrofuran and/or metabolite present in the sample to form antibody-analyte complexes.
  • the mobile phase can be combined with sample prior to application to the test strip or other solid support.
  • antibody can bind to nitrofuran and/or metabolite present in the sample prior to contact with the test strip.
  • the test strip includes a stationary-phase support strip, which may be part of the same strip as the mobile-phase composition, or on a separate strip in fluid flow contact with the first strip.
  • the support strip has a first membrane end in contact with the mobile-phase composition and a second membrane end that may be in contact with an optional disposal zone. Lateral-capillary flow of the sample is from the first membrane end to the second membrane end.
  • the one or more test zones may include a binder, such as a representative analyte or analogue thereof, which captures unbound labeled receptor.
  • One * or more optional control zones may also be on the stationary-phase membrane.
  • the control zone may contain receptor for the analyte receptor, for example, antibody to the particular receptor, such as anti-species antibody, for binding with both analyte-bound receptor and excess unbound ⁇ receptor.
  • the control zone may be involved in an independent reaction that informs the user that the test is complete and includes consistent visual indicators, such as color development, for comparison to the test zone.
  • the control zone can generate signal either on contact with sample or on contact with specific test material, such as labeled receptor, such as when the control zone includes an anti-species antibody or one of the several useful antibody binders known in the art including protein A, protein G or recombinant varieties of proteins A and G.
  • test zone binders examples include nitrofurans, nitrofuran metabolites, acrylonitrile derivatives of a nitrofuran, or analogues thereof and NP nitrofuran derivatives.
  • binders can be either synthetically derived or, in some cases, the related naturally occurring species.
  • Such a binder may be disposed on the test zone portion of the membrane for example by spraying. Prior to spraying, said binder can be conjugated to an attachment or carrier protein.
  • Suitable attachment proteins are known to those skilled in the art to be proteins that bind readily to solid supports, such supports that include nitrocellulose.
  • a useful attachment protein includes a carrier protein, i.e., a protein commonly used in conjunction with an immunogen, such as generally water soluble proteins with multiple accessible amino groups including albumin, e.g., bovine serum albumin (BSA), ovalbumin (OVA), keyhole limpet hemocyanin (KLH) and thyroglobulin (THG).
  • BSA bovine serum albumin
  • OVA ovalbumin
  • KLH keyhole limpet hemocyanin
  • TGF thyroglobulin
  • the lateral flow test device and method can also be in a sandwich assay format or an inhibition/competitive format. Multiple test zones can be utilized, for example to detect the presence of multiple analytes using multiple specific antibodies. In such multiple analyte tests, multiple control lines may or may not be required.
  • An embodiment includes a lateral flow assay that is capable of rapidly detecting one or more nitrofurans and/or metabolites such as tissue bound metabolites of nitrofurans in a sample.
  • lateral flow assay formats can include those described in U.S. Patents 7,097,983; 6,319,466; 6,475,805; and 5,985,675, the teachings of which are incorporated herein by reference.
  • Lateral flow test results can be interpreted visually or by use of a reader, or analyzer, such as a ROSA® reader (ROSA is a registered trademark of Charm Sciences, Inc. Lawrence, MA).
  • a reader or analyzer
  • Other reader/analyzer examples include fluorometers, luminometers, bar code readers, radiation detectors (such as scintillation counters), UV detectors, infrared detectors, electrochemical detectors or optical readers, such as spectrophotometers.
  • the reader can be used to distinguish between one or more test zones and one or more control zones or simply to determine a relative change in the test zone.
  • the reader is a ROSA reader.
  • the analyzer is an optical reader, e.g., the reader described in U.S. Patent No. 6,124,585, issued September 26, 2000, hereby incorporated by reference.
  • a radiolabeled tracer can be employed with the antibody.
  • an IGGSORB® tablet (IGGSORB is a registered trademark of The Enzyme Center, Lawrence, Massachusetts) containing a lyophilized preparation of protein A fixed to the cell walls of inactivated Staphylococcus aureas, is added to a test tube along with 300 ⁇ L of deionized water. An appropriate amount of antibody is added to the tube and the tube is mixed.
  • an amount of buffer for example 5ml of MSU-EB (from Charm Sciences, Inc.) is added to the tube along with 5 ⁇ L of appropriate radiolabeled tracer and the tube is again mixed. The tube is incubated for five minutes at 40 0 C and then centrifuged for 5 minutes at 3400rpm. The supernatant is poured off and scintillation fluid is added for tracer detection.
  • test tubes were again capped, shaken by hand and vortexed (1Ox). 2mL of ethyl acetate was then added, the test tubes capped, shaken by hand and then vortexed for 30 seconds. The mixture was then centrifuged at 250 g for 1 minute. 1.0 mL was removed from the upper organic layer and transferred to another 13 mm test tube. The organic extract was dried by placing the tube in a 55-60 0 C heating block with air flow directed into the tubes. Drying time was about 10 minutes. 0.4mL n-heptane was added to the dried residue, the tubes mixed.
  • Sample buffer (1OmM sodium phosphate with 0.05% Tween 20, pH 7.2) was then added and the mixture vortex (1Ox) and centrifuged at 250 g for 5 minutes. 300 uL was removed from the lower aqueous layer and transferred to an Eppendorf tube for ELISA in a 100 ⁇ l sample well.
  • a solution of AMOZ (30.2 mg, 0.15 mmole) in 0.75 ml of acetonitrile was mixed with a solution of 4-NBA (27.2 mg, 0.18 mmole) in 0.75 ml of acetonitrile and treated with 0.12 ml of 1 N HCl.
  • the reaction mixture was stirred at room temperature overnight and concentrated to induce crystallization.
  • the suspension was filtered and the yellow solid retentate was washed with 1 ml of acetonitrile and air-dried to give the desired product (20.8 mg, 0.062 mmole).
  • Another crop of product (15.8 mg, 0.047 mmole) was obtained by recrystallization from the filtrate.
  • HPLC analysis was carried out as in the analysis of 4-NP- AOZ, showing a single peak with retention time of 6.6 min.
  • the pure compound showed similar UV/vis spectrum with a major peak absorbance around 323 nm and a minor peak absorbance around 230 nm in the same solvent system, characteristic of the common 4- nitrophenyl-hydrazone chromophore present.
  • a solution of furazolidone (FZD, 10 ug, 0.044 umole) in 0.5 ml of 1% DMF/water solution was treated with 1 ml of 1 N HCl and 50 ul of 40 mM 4-NBA (2 umole) in DMSO.
  • the solution was heated on a heating block at 80 0 C for 15 min, neutralized with 1 ml of 1 M K 2 HPO 4 /O.8 N NaOH and extracted with 2 ml of ethyl acetate.
  • One ml of solvent extract was withdrawn and dried in 6O 0 C water bath under air flow for 10 minutes.
  • the dried residue was first dissolved with 50 ul of acetonitrile and then diluted with 450 ul of water to give a sample solution A for HPLC analysis.
  • Two fifths (200 ul) of the sample solution was injected onto an HPLC system equipped with a photodiode array detector and driven by software which is capable of system control, monitoring, spectral analysis of the peaks and data processing/reporting.
  • the HPLC column was a reverse phase column (PLRP-S, 5 urn,
  • Example 2 100 A°, 4 x 150 mm) as described in Example 2.
  • the HPLC chromatogram was monitored at 323 nm for the presence of 4-NP-AOZ which has a major peak absorbance at 323.9 nm and a minor peak absorbance at 231.6 nm.
  • two other sample solutions B and C were prepared in the same manner except without the addition of FZD or 4-NBA, respectively.
  • FZD has peak absorbance at 366.6 and 261.0 nm. Its absorbance at 323 nm is about ! ⁇ as intense as the 366.6 nm peak.
  • 4- NBA has peak absorbance at 266.9 nm. Its absorbance at 323 nm is about 6% of the peak intensity.
  • Sample solution A chromatogram contained predominantly the 4-NP-AOZ peak (6.9 min) and the excess of 4-NBA (13.3 min). Very little of unreacted FZD (peak 4.20 min) was detected.
  • Sample solution B chromatogram contained essentially only the 4-NBA peak at 13.2 minutes was detectable in the sample solution B chromatogram. No FZD and 4-NPAOZ peaks were detectable indicating that no 4-NP-AOZ can be generated in the absence of FZD.
  • Sample solution C chromatogram contained a peak at 4.18 minutes (FZD). A completely flat baseline was observed beyond 5.5 min of elution indicating that no 4-NP- AOZ can be generated in the absence of 4-NBA.

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Abstract

L'invention concerne un procédé pour détecter le nitrofurane qui comprend une hydrolyse acide rapide d'un échantillon pour obtenir un échantillon approprié pour une mise à l'essai en moins de 16 heures.
PCT/US2008/003750 2007-03-21 2008-03-21 Procédé pour détecter le nitrofurane WO2008115580A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US91932507P 2007-03-21 2007-03-21
US60/919,325 2007-03-21
US92117107P 2007-03-30 2007-03-30
US60/921,171 2007-03-30

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WO2008115580A2 true WO2008115580A2 (fr) 2008-09-25
WO2008115580A3 WO2008115580A3 (fr) 2008-12-11

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102183634A (zh) * 2011-03-04 2011-09-14 河北省兽药监察所 快速检测四种硝基呋喃类药物的免疫纳米金试纸条
CN103698435A (zh) * 2013-12-30 2014-04-02 江苏省环境监测中心 硝基呋喃类代谢产物的超高效液相色谱-三重四级杆质谱的检测方法
CN104880523A (zh) * 2015-04-28 2015-09-02 衢州出入境检验检疫局综合技术服务中心 高效液相色谱串联质谱法测定蜂蜡中硝基呋喃类代谢物的方法
US10759845B2 (en) 2018-08-09 2020-09-01 Jiangnan University Hybridoma cell strain secreting nifursolol residue marker monoclonal antibody
CN113960013A (zh) * 2021-11-08 2022-01-21 北京同仁堂健康（大连）海洋食品有限公司 一种基于Br辅助SERS检测硝基呋喃类药物代谢物的方法
CN115014890A (zh) * 2022-05-18 2022-09-06 深圳职业技术学院 样品处理方法和硝基呋喃类代谢物的测定方法
CN115165868A (zh) * 2022-07-26 2022-10-11 中农康正技术服务有限公司 一种肉制品中呋喃它酮代谢物的检测方法和装置

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
COOPER ET AL.: 'Production and characterization of polyclonal antibodies to a derivative of 3-amino 2-oxozolidione, a metabolite of the nitrofurazalidone' ANALYTICA CHEMICA ACTA vol. 520, 2004, pages 79 - 86 *
HOGENBOOM ET AL.: 'The use of hepatocytes to study the nature of protein bound metabolites of Furazolidone: a new analytical method for their detection' FD. CHEM. TOXIC. vol. 29, no. 5, 1991, pages 321 - 328 *
HORNE ET AL.: 'Analysis of protein bound metabolites of furazolidone and frualtadone in pig liver by high performance liquid chromatography and liquid chromatography mass spectrometry' ANALYST vol. 121, 1996, pages 1463 - 1468 *
VASS ET AL.: 'Production and characterization of monoclonal antibodies for detection of AOZ, a tissue bound metabolite of furazolidone' 2002, pages 300 - 310, XP002995939 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102183634A (zh) * 2011-03-04 2011-09-14 河北省兽药监察所 快速检测四种硝基呋喃类药物的免疫纳米金试纸条
CN103698435A (zh) * 2013-12-30 2014-04-02 江苏省环境监测中心 硝基呋喃类代谢产物的超高效液相色谱-三重四级杆质谱的检测方法
CN103698435B (zh) * 2013-12-30 2015-06-24 江苏省环境监测中心 硝基呋喃类代谢产物的超高效液相色谱-三重四级杆质谱的检测方法
CN104880523A (zh) * 2015-04-28 2015-09-02 衢州出入境检验检疫局综合技术服务中心 高效液相色谱串联质谱法测定蜂蜡中硝基呋喃类代谢物的方法
US10759845B2 (en) 2018-08-09 2020-09-01 Jiangnan University Hybridoma cell strain secreting nifursolol residue marker monoclonal antibody
US10882896B2 (en) 2018-08-09 2021-01-05 Jiangnan University Hybridoma cell strain secreting nifursolol residue marker monoclonal antibody
CN113960013A (zh) * 2021-11-08 2022-01-21 北京同仁堂健康（大连）海洋食品有限公司 一种基于Br辅助SERS检测硝基呋喃类药物代谢物的方法
CN115014890A (zh) * 2022-05-18 2022-09-06 深圳职业技术学院 样品处理方法和硝基呋喃类代谢物的测定方法
CN115165868A (zh) * 2022-07-26 2022-10-11 中农康正技术服务有限公司 一种肉制品中呋喃它酮代谢物的检测方法和装置

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