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Determination of Ibuprofen, Ketoprofen, Diclofenac and Phenylbutazone In Determination of ibuprofen, ketoprofen, diclofenac and phenylbutazone in bovine milk by gas chromatography tandem mass spectrometry Geraldine Dowling, Pasquale Gallo, Serena Fabbrocino, Luigi Serpe, Liam Regan To cite this version: Geraldine Dowling, Pasquale Gallo, Serena Fabbrocino, Luigi Serpe, Liam Regan. Determina- tion of ibuprofen, ketoprofen, diclofenac and phenylbutazone in bovine milk by gas chromatogra- phy tandem mass spectrometry. Food Additives and Contaminants, 2008, 25 (12), pp.1497-1508. 10.1080/02652030802383160. hal-00577318 HAL Id: hal-00577318 https://hal.archives-ouvertes.fr/hal-00577318 Submitted on 17 Mar 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Food Additives and Contaminants For Peer Review Only Determination of ibuprofen, ketoprofen, diclofenac and phenylbutazone in bovine milk by gas chromatography tandem mass spectrometry Journal: Food Additives and Contaminants Manuscript ID: TFAC-2007-447.R1 Manuscript Type: Special Issue Date Submitted by the 26-Jun-2008 Author: Complete List of Authors: Dowling, Geraldine; The State Laboratory Gallo, Pasquale; Istituto Zooprofilatico Sperimentale del Mezzogiorno, Chemistry Fabbrocino, Serena; Istituto Zooprofilatico Sperimentale del Mezzogiorno,, Chemistry Serpe, Luigi; Istituto Zooprofilatico Sperimentale del Mezzogiorno, Chemistry Regan, Liam; The State Laboratory, Veterinary Toxicology Methods/Techniques: Chromatography - GC/MS Additives/Contaminants: Veterinary drug residues Food Types: Milk http://mc.manuscriptcentral.com/tfac Email: [email protected] Page 1 of 22 Food Additives and Contaminants 1 2 3 4 Determination of ibuprofen, ketoprofen, diclofenac and phenylbutazone 5 6 in bovine milk by gas chromatography tandem mass spectrometry 7 8 9 Geraldine Dowling a, Pasquale Gallo b, Serena Fabbrocino b, Luigi Serpe b and Liam 10 11 Regan a 12 13 14 a 15 The State Laboratory, Backweston Laboratory Complex, Young’s Cross, Celbridge, 16 Co. Kildare,For Ireland Peer Review Only 17 18 b Istituto Zooprofilatico Sperimentale del Mezzogiorno, Via Salute 2, 80055 Portici 19 20 (Naples), Italy 21 22 23 24 25 Abstract 26 27 28 A method has been developed to analyse for ibuprofen (IBP), ketoprofen (KPF), 29 30 diclofenac (DCF) and phenylbutazone (PBZ) residues in bovine milk. Milk samples 31 were extracted with acetonitrile and sample extracts were purified on Isolute TM C 32 18 33 solid phase extraction cartridges. Aliquots were analysed by gas chromatography 34 35 tandem mass spectrometry (GC-MS/MS). The method was validated in bovine milk, 36 37 according to the criteria defined in Commission Decision 2002/657/EC. The decision 38 -1 39 limit (CC α) was 0.59, 2.69, 0.90 and 0.70 ng ml , respectively, for IBP, KPF, DCF 40 and PBZ and for the detection capability (CC β) values of 1.01, 4.58, 1.54 and 1.19 ng 41 42 ml -1 respectively, were obtained. The measurement uncertainty of the method was 43 44 17.8, 80.9, 28.2 and 20.2 % for IBP, KPF, DCF and PBZ. Fortifying bovine milk 45 46 samples (n = 18) in three separate assays, show the accuracy of the method to be 47 48 between 104 and 112 %. The precision of the method, expressed as RSD values for 49 the within-lab reproducibility at the three levels of fortification (5, 7.5 and 10 ng ml -1) 50 51 was less than 8 % for IBP, DCF and PBZ respectively. Poor precision was obtained 52 53 for KPF with an RSD value of 28 %. 54 55 56 Keywords : Ibuprofen; Ketoprofen; Diclofenac; Phenylbutazone; Bovine Milk; 57 58 Method Validation 59 60 1 http://mc.manuscriptcentral.com/tfac Email: [email protected] Food Additives and Contaminants Page 2 of 22 1 2 3 Introduction 4 5 6 7 Phenylbutazone (PBZ), ibuprofen (IBP), ketoprofen (KPF) and diclofenac (DCF) are 8 9 non-steroidal anti-inflammatory drugs (NSAIDs). The molecular structure of these 10 11 compounds is shown in Fig. 1. NSAIDs are used widely in veterinary medicine in the 12 treatment of food producing animals. Depending on their heterogeneous molecular 13 14 structures the NSAIDs can be classified into four main sub-classes: (a) salicyclic acid 15 16 derivatives;For (b) propionic Peer acid derivatives; Review (c) pyrazole Onlyderivatives and (d) aniline 17 18 derivatives including both anthranilic acid derivatives and nicotinic acid derivatives. 19 PBZ is a pyrazole derivative, IBP and KPF are propionic acid derivatives and DCF is 20 21 an aniline derivative. 22 23 24 In the USA a survey was carried out involving 2000 veterinarians whose practices 25 26 dealt 50% of the time with food producing animals [U.S Code of Federal Regulations, 27 28 1988]. The survey showed that 93 % of veterinarians use NSAIDs on a regular basis. 29 Dairy practitioners reported more frequent use of NSAIDs than did beef practitioners. 30 31 Overall, veterinarians indicated that NSAIDs were an important group of compounds 32 33 which were routinely used for the treatment of food producing animals [Kopcha, et 34 35 al ., 1992]. According to EU law, all substances for veterinary use need to be included 36 in Annexes 1-3 of Regulation 2377/90 [European Commission, 1990]. This regulation 37 38 establishes lists of compounds that have a fixed MRL (Annex I), that need no MRL 39 40 (Annex II) or that have a provisional MRL (Annex III). PBZ and IBP are compounds 41 42 that have not been included in Annexes 1-3 and have no maximum residue limit 43 44 (MRL) established. Substances that have no MRL established are prohibited for use in 45 food producing animals. DCF is listed in Annex I and a provisional MRL has been set 46 47 for different animal species and target matrices. DCF is however prohibited for use in 48 49 milk producing animals. KPF is listed in Annex II and is allowed for the application 50 51 to species that produce milk but are not intended for human consumption. NSAIDs 52 can cause adverse health effects in humans such as aplastic anaemia, gastrointestinal 53 54 disorders and agranulocytosis [Insel, et al ., 1990] and changes in renal function 55 56 [Goodman , et al ., 1992]. Longterm exposure to PBZ has caused kidney tumors in 57 58 mice and liver tumors in rats [Kari, et al ., 1995]. The widespread use of NSAIDs 59 presents a potential risk to the consumer if food containing residues enter the food 60 2 http://mc.manuscriptcentral.com/tfac Email: [email protected] Page 3 of 22 Food Additives and Contaminants 1 2 3 chain so there is a need for the development of methods to monitor compliance with 4 5 legislation in the EU in a variety of animal tissues and products. 6 7 8 In the determination of NSAIDs in animal tissues PBZ has been shown to be extracted 9 10 from equine plasma using acetonitrile [Hardee, et al ., 1982; Neto, et al ., 1996] or 11 12 ethyl acetate [Grippa, et al ., 2000], from equine urine with methanol [Stanley, et al ., 13 2007] or a mixture of dichloromethane:ethanol solution [Neto, et al ., 1996]. PBZ has 14 15 been shown to be extracted from bovine plasma using acetonitrile [Miksa, et al ., 16 For Peer Review Only 17 2005; Fiori, et al ., 2004] or a straight forward ultra-centrifugation procedure [De 18 19 Veau, et al ., 1999]. IBP, KPF and DCF has been shown to be extracted from bovine 20 plasma using acetontrile [Miksa, et al ., 2005]. PBZ has been shown to be extracted 21 22 from ovine, equine, and porcine muscle using a mixture of ethyl acetate: methanol 23 24 and DL-dithio-threitol [Clarke, et al ., 2002]. PBZ has been shown to be extracted 25 26 from bovine kidney using a mixture of water: ammonium hydroxide [Clarke, et al ., 27 28 2002]. PBZ has been shown to be extracted from bovine milk with a mixture of 29 ethanol: ammonia [Martin, et al ., 1983]. KPF has been shown to be extracted from 30 31 bovine milk using acetonitrile [Daeseleire, et al ., 2003]. The incorporation of a 32 33 hydrolysis step at the beginning of the extraction procedure for the determination of 34 35 NSAIDs is also reported in the literature. This hydrolysis step allows the deactivation 36 of plasma bound proteins and the release of the protein bound NSAID residues. After 37 38 hydrolysis PBZ has been shown to be extracted from bovine plasma using 39 40 dichloromethane [Singh, et al ., 1991], from equine plasma with a mixture of 41 42 dichloromethane:n-hexane:diethyl ether solution [Hines, et al ., 2004], porcine, ovine, 43 44 bovine and caprine urine were extracted with chloroform [Igualada and Moragues, 45 2005] and equine urine was extracted with dichloromethane [Singh, et al ., 1991] or 46 47 diethyl ether [Gonzalez, et al ., 1996] for the determination of PBZ. After hydrolysis 48 49 or solvent extraction, solid phase extraction [SPE] is often used in the purification of 50 51 extracts containing NSAIDs. Bovine plasma has been shown to be purified using C 18 52 SPE for the determination of PBZ and DCF [Gowik, et al ., 1998], IBP, KPF, DCF 53 54 and PBZ [Vinci, et al., 2006] and IBP, KPF and DCF [De Jong, et al ., 1989]. Plasma 55 56 from pigs and rabbits was purified using this approach to determine IBP, KPF, DCF 57 58 and PBZ [Vinci, et al., 2006].
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