Pharmacokinetics, Pharmacodynamics, Metabolism, Toxicology and Residues of Phenylbutazone in Humans and Horses. Peter Lees, Pierre-Louis Toutain
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Pharmacokinetics, pharmacodynamics, metabolism, toxicology and residues of phenylbutazone in humans and horses. Peter Lees, Pierre-Louis Toutain To cite this version: Peter Lees, Pierre-Louis Toutain. Pharmacokinetics, pharmacodynamics, metabolism, toxicology and residues of phenylbutazone in humans and horses.. Veterinary Journal, Elsevier, 2013, 196 (3), pp.294- 303. 10.1016/j.tvjl.2013.04.019. hal-02648884 HAL Id: hal-02648884 https://hal.inrae.fr/hal-02648884 Submitted on 29 May 2020 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. The Veterinary Journal 196 (2013) 294–303 Contents lists available at SciVerse ScienceDirect The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl Review Pharmacokinetics, pharmacodynamics, metabolism, toxicology and residues of phenylbutazone in humans and horses ⇑ Peter Lees a, Pierre-Louis Toutain b, a Royal Veterinary College, Hawkshead Campus, Hatfield, Hertfordshire AL9 7TA, UK b École National Vétérinaire de Toulouse, UMR 1331 Toxalim INRA, 23 Chemin des Capelles-BP 87614, 31076 Toulouse Cedex 03, France article info abstract Article history: The presence of horse meat in food products destined for human consumption and labelled as beef has Accepted 28 April 2013 raised several concerns of public interest. This review deals solely with one aspect of these concerns; samples of equine tissue from horses destined for the human food chain have tested positive for the Keywords: non-steroidal anti-inflammatory drug, phenylbutazone. The safety of some or all such foods for human Equine consumers is a major concern, because it was shown many years ago that phenylbutazone therapy in Human humans can be associated with life threatening blood dyscrasias. Phenylbutazone As an initial basis for assessing the potential toxicity of foods containing phenylbutazone and its Oxyphenbutazone metabolites, this article reviews (1) the pharmacokinetic, pharmacodynamic, metabolic and toxicological Pharmacology Toxicology profiles of phenylbutazone, with particular reference to horses and humans; (2) toxicity data in labora- Residues tory animals; (3) phenylbutazone residues in food producing species, and (4) as a preliminary assess- ment, the potential hazard associated with the consumption of horse meat containing phenylbutazone and its metabolites. Since phenylbutazone cannot be classified as a carcinogenic substance in humans, and noting that blood dyscrasias in humans are likely to be dose and treatment duration-dependent, the illegal and erra- tic presence of trace amount residues of phenylbutazone in horse meat is not a public health issue. Ó 2013 Elsevier Ltd. All rights reserved. Introduction Phenylbutazone has brought major welfare benefits to horses as an analgesic/anti-inflammatory agent over more than 50 years of The presence of horse meat in burgers and other meat products clinical use. At the same time, its availability has become so exten- labelled as beef and destined for human consumption is of major sive in many countries that proper control of its use, to ensure that concern on several counts. One aspect of interest to the public horses treated with the drug do not enter the human food chain, and regulatory authorities is the detection of phenylbutazone in poses a significant challenge, which can and must be met. It is a a very small percentage of carcasses destined for human consump- low cost drug available in granule, paste and injectable formula- tion. This review provides an update on current knowledge of the tions for equine use, but is not available for use in any other food pharmacological, toxicological and residue depletion profiles of producing species. It was formerly available in oral formulations phenylbutazone, with particular reference to published data in for human use. horses, humans and laboratory animals, as a relevant background This review makes no attempt to undertake a full risk analysis to assessing the safety for consumers of foods containing relating to the presence of phenylbutazone in low concentrations phenylbutazone and its metabolites. The review does not seek to in horse or processed meat samples destined for human consump- provide a full quantitative risk analysis. This will become possible tion. This will be appropriate, when further residues data become when further data on the incidence and quantitative levels of phe- available from surveillance to form the basis of a quantitative risk nylbutazone and its metabolites become available from on-going evaluation. studies. Mutagenicity, genotoxicity and carcinogenicity of phenyl- butazone are reviewed principally on the basis of cell culture and History of phenylbutazone use laboratory animal studies. An indication is given when the data are limited in scope or interpretation is equivocal. Phenylbutazone was introduced into human medicine in 1949 as a novel agent of the non-steroidal anti-inflammatory drug (NSAID) class for use in the treatment of acute and chronic inflam- ⇑ Corresponding author. Tel.: +33 561193912. matory pain, notably various forms of arthritis (Von Rechenberg, E-mail address: [email protected] (P.-L. Toutain). 1962). It proved to be an excellent analgesic and, for 30 years, 1090-0233/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tvjl.2013.04.019 P. Lees, P.-L. Toutain / The Veterinary Journal 196 (2013) 294–303 295 was used extensively, for example, as the drug of choice for treat- phenylbutazone is available only for oral administration and for a ment of arthritides. The phenylbutazone pioneer product, Butaco- single indication, chronic laminitis. The early literature is extensive te, was licensed originally to Geigy Pharmaceuticals and and has been summarised in several reviews (Gabel et al., 1977; subsequently to Novartis Pharmaceuticals. The manufacturers’ rec- Lees and Higgins, 1985; Tobin et al., 1986; Lees et al., 2004; Soma ommended dosage was: (1) Adults: For the initial 48 h, 400– et al., 2011). After IV dosing, clearance and elimination half-life are 600 mg daily in divided doses; thereafter, reduce to the minimum of the order of 16–26 mL/h/kg and 4–6 h, respectively (Lees and amount necessary, usually 200–300 mg in divided doses; at the Higgins, 1985; Lees et al., 1986a; Maitho et al., 1986). Phenylbuta- time of its introduction in 1949, a higher dose of 1 g per subject zone is well absorbed after oral dosing as granules, paste or bolus per day was used; and (2) Elderly subjects: Always use the mini- formulations. Several metabolites have been identified; the princi- mum effective dose. pal ones are oxyphenbutazone and c-hydroxyphenylbutazone. In the 1980s, severe restrictions were placed on phenylbuta- These two metabolites are of particular interest, since they possess zone use in humans. The later history of this product was briefly analgesic/anti-inflammatory properties and thus contribute (to an as follows: (1) 1984: the 200 mg tablets were discontinued for unknown but probably small/moderate degree) to the pharmaco- commercial reasons; (2) May 1984: the product licence was re- logical actions of phenylbutazone. For both metabolites, urine stricted to the treatment of ankylosing spondylitis, for hospital concentrations are much higher than those in plasma. use only; and (3) September 2002: the 100 mg tablets were with- The bioavailability of phenylbutazone is in the range of 69–91% drawn from the market for commercial reasons. Peak use in the (Chay et al., 1984; Lees and Higgins, 1985, 1986; Maitho et al., USA was in 1974, when 14 million prescriptions were issued and 1986; Smith et al., 1987; Delbeke et al., 1993). These and several this decreased to 2 million in 1984. In that year the safety of phe- other studies demonstrate that the rate of absorption varies con- nylbutazone was examined by a USA Food and Drugs Administra- siderably between and within horses and also according to tion (FDA) advisory committee (Faich, 1987). whether the horse has free access to feed (grass, hay, pelleted feed) Curtailment of the use of phenylbutazone in the 1980s resulted at the time of oral dosing (Gerring et al., 1981; Maitho et al., 1986). from the recognition that it induces, very rarely, blood dyscrasias, If feed is withheld for 3–4 h both before and after dosing, the max- including aplastic anaemia, leukopenia, agranulocytosis and imum concentration in plasma (Cmax) occurs (Tmax) at 4–6 h thrombocytopenia, in some cases leading to death. Hypersensitiv- and is usually characterised by a single peak. If, on the other hand, ity reactions of the serum sickness type were also reported. Fatal- the horse has full access to feed at the time of oral dosing, there is ities were associated with use in humans at manufacturers’ usually a very small initial peak in plasma concentration after 1– recommended dose rates. Nevertheless, therapeutic use was still 2 h, then a return to baseline, followed by a much larger secondary allowed in individual patients, under specialist control and with absorption phase from 10 to 24 h, giving a mean Tmax of 12–14 h regular blood profile monitoring. Thus, in some countries, phenyl- (Maitho et al., 1986). The difference between the two absorption butazone licensed to generic companies has continued to be used. profiles (fed vs. non-fed) has been ascribed to adsorption of phe- Phenylbutazone was introduced into veterinary medicine in the nylbutazone onto the fibrous component of hay/grass/nuts, ren- 1950s, and has now been used, to a limited degree, in the dog and, dering the adsorbed fraction unavailable for absorption until the very extensively, in the horse for >50 years.