Comparative and Veterinary Pharmacology pp 315-339

Part of the Handbook of Experimental Pharmacology book series (HEP, volume 199)

Veterinary Medicines and Competition Animals: The Question of Medication Versus Doping Control

Chapter

Abstract

In racing and other equine sports, it is possible to increase artificially both the physical capability and the presence of a competitive instinct, using drugs, such as anabolic steroids and agents stimulating the central nervous system. The word doping describes this illegitimate use of drugs and the primary motivation of an equine anti-doping policy is to prevent the use of these substances. However, an anti-doping policy must not impede the use of legitimate veterinary medications and most regulatory bodies in the world now distinguish the control of illicit substances (doping control) from the control of therapeutic substances (medication control). For doping drugs, the objective is to detect any trace of drug exposure (parent drug or metabolites) using the most powerful analytical methods (generally chromatographic/mass spectrometric techniques). This so-called “zero tolerance rule” is not suitable for medication control, because the high level of sensitivity of current screening methods allows the detection of totally irrelevant plasma or urine concentrations of legitimate drugs for long periods after their administration. Therefore, a new approach for these legitimate compounds, based upon pharmacokinetic/pharmacodynamic (PK/PD) principles, has been developed. It involves estimating the order of magnitude of the irrelevant plasma concentration (IPC) and of the irrelevant urine concentration (IUC) in order to limit the impact of the high sensitivity of analytical techniques used for medication control. The European Horserace Scientific Liaison Committee (EHSLC), which is the European scientific committee in charge of harmonising sample testing and policies for racehorses in Europe, is responsible for estimating the IPCs and IUCs in the framework of a Risk Analysis. A Risk Analysis approach for doping/medication control involves three sequential steps, namely risk assessment, risk management, and risk communication. For medication control, the main task of EHLSC in the risk management procedure is the establishment of harmonised screening limits (HSL).The HSL is a confidential instruction to laboratories from racing authorities to screen in plasma or urine for the presence of drugs commonly used in equine medication. The HSL is derived from the IPC (for plasma) or from the IUC (for urine), established during the risk assessment step. The EHSLC decided to keep HSL confidential and to inform stakeholders of the duration of the detection time (DT) of the main medications when screening is performed with the HSL. A DT is the time at which the urinary (or plasma) concentration of a drug, in all horses involved in a trial conducted according to the EHSLC guidance rules, is shown to be lower than the HSL when controls are performed using routine screening methods. These DTs, as issued by the EHSLC (and adopted by the Fédération Equestre Internationale or FEI) provide guidance to veterinarians enabling them to determine a withdrawal time (WT) for a given horse under treatment. A WT should always be longer than a DT because the WT takes into account the impact of all sources of animal variability as well as the variability associated with the medicinal product actually administered in order to avoid a positive test. The major current scientific challenges faced in horse doping control are those instances of the administration of recombinant biological substances (EPO, GH, growth factors etc.) having putative long-lasting effects while being difficult or impossible to detect for more than a few days. Innovative bioanalytical approaches are now addressing these challenges. Using molecular tools, it is expected in the near future that transcriptional profiling analysis will be able to identify some molecular “signatures” of exposure to doping substances. The application of proteomic (i.e. the large scale investigation of protein biomarkers) and metabolomic (i.e. the study of metabolite profiling in biological samples) techniques also deserve attention for establishing possible unique fingerprints of drug abuse.

Keywords

Detection time Doping Horse Irrelevant urine/plasma concentration Medication control Risk analysis Threshold Withdrawal time 

References

  1. Aguilera R, Becchi M, Mateus L, Popot MA, Bonnaire Y, Casabianca H, Hatton CK (1997) Detection of exogenous hydrocortisone in horse urine by gas chromatography-combustion-carbon isotope ratio mass spectrometry. J Chromatogr B Biomed Sci Appl 702:85–91CrossRefPubMedGoogle Scholar
  2. Authié E, Garcia P, Popot MA, Toutain PL, Doucet MY (2009) Effect of an endurance-like exercise on the disposition and detection time of phenylbutazone and dexamethasone in the horse: application to medication control. Equine Vet J (in press)Google Scholar
  3. Bailly-Chouriberry L, Chu-Van E, Pinel G, Garcia P, Popot MA, Andre-Fontaine G, Bonnaire Y, Le Bizec B (2008a) Detection of secondary biomarker of met-eGH as a strategy to screen for somatotropin misuse in horseracing. Analyst 133:270–276CrossRefPubMedGoogle Scholar
  4. Bailly-Chouriberry L, Pinel G, Garcia P, Popot MA, Le Bizec B, Bonnaire Y (2008b) Identification of recombinant equine growth hormone in horse plasma by LC-MS/MS: a confirmatory analysis in doping control. Anal Chem 80:8340–8347CrossRefPubMedGoogle Scholar
  5. Barragry T (2006) Continuing education – Doping and drug detection times in horses: new data for therapeutic agents. Irish Vet J 59:394–398Google Scholar
  6. de Kock SS, Boshoff R, Jogi P, Swanepoel BC (2004) An investigation of performance enhancing drug use in pigeon racing and the development of suitable faeces testing methodology. In: Albert PH, Morton T, Wade JF (eds) 15th International Conference of Racing Analysts and Veterinarians. R&W Communications, Dubai, UAE, pp 359–364Google Scholar
  7. Dunnett N (1994) Sampling procedure – sampling preparation (chain of custody). In: Kallings U, Bondesson U, Houghton E (eds) 10th International Conference of Racing Analysts and Veterinarians. R&W, Stockholm, Sweden, pp 313–315Google Scholar
  8. Dunnett M, Lees P (2003) Trace element, toxin and drug elimination in hair with particular reference to the horse. Res Vet Sci 75:89–101CrossRefPubMedGoogle Scholar
  9. Guan F, Uboh CE, Soma LR, Birks E, Chen J, Mitchell J, You Y, Rudy J, Xu F, Li X, Mbuy G (2007) LC-MS/MS method for confirmation of recombinant human erythropoietin and darbepoetin alpha in equine plasma. Anal Chem 79:4627–4635CrossRefPubMedGoogle Scholar
  10. Hall DJ (2004) ISO/IEC 17025: a guide to interpretation within the AORC. In: Albert PH, Morton T, Wade JF (eds) 15th International Conference of Racing Analysts and Veterinarians. R&W Communications, Dubai, UAE, pp 199Google Scholar
  11. Higgins AJ (2006) From ancient Greece to modern Athens: 3000 years of doping in competition horses. J Vet Pharmacol Ther 29:4–8CrossRefGoogle Scholar
  12. Hinchcliff KW, Muir WW III (1991) Pharmacology of furosemide in the horse: a review. J Vet Intern Med 5:211–218CrossRefPubMedGoogle Scholar
  13. Hinchcliff KW, Morley PS, Guthrie AJ (2009) Efficacy of furosemide for prevention of exercise-induced pulmonary hemorrhage in thoroughbred racehorses. J Am Vet Med Assoc 235:76–82CrossRefPubMedGoogle Scholar
  14. Hodgson D, Howe S, Jeffcott L, Reid S, Mellor D, Higgins A (2005) Effect of prolonged use of altrenogest on behaviour in mares. Vet J 169:322–325CrossRefPubMedGoogle Scholar
  15. Houghton E (1994) The threshold values -current and future problems. In: Kallings P, Bondesson U, Houghton E (eds) 10th International Conference of Racing Analysts and Veterinarians. R&W, Stockholm, Sweden, pp 297–302Google Scholar
  16. Houghton E, Crone DL (2000) The approaches adopted by the racing industry to address endogenous substances and substances of dietary origin. In: Williams RB, Houghton E, Wade JF (eds) 13th International Conference of Racing Analysts and Veterinarians. R&W, Cambridge, UK, pp 23–28Google Scholar
  17. Houghton E, Williams RB, Toutain PL (2004) Therapeutic substances – The road to reform the European approach. In: Albert PH, Morton T, Wade JF (eds) 15th International Conference of Racing Analysts and Veterinarians. R&W Communications, Dubai, United Arab Emirates, pp 16–18Google Scholar
  18. Lakhani KH, Lambert M, Sluyter F, Devolz R, Maylin G, Higgins AJ (2004) Estimation of the critical threshold value for presence of salicylic acid in the urine of thoroughbred horses. In: Albert PH, Morton T, Wade JF (eds) 15th International Conference of Racing Analysts and Veterinarians. R&W Communications, Dubai, United Arab Emirates, pp 67–77Google Scholar
  19. Lees P, Taylor JB, Higgins AJ, Sharma SC (1986) Phenylbutazone and oxyphenbutazone distribution into tissue fluids in the horse. J Vet Pharmacol Ther 9:204–212CrossRefPubMedGoogle Scholar
  20. Lilliehook I, Schuback-Nosell K, Essen-Gustavsson B et al (2004) Haematological and bone marrow responses after administration of recombinant human arythropoietin (rhEPO) to horses. In: Albert PH, Morton T, Wade JF (eds) 15th International Conference of Racing Analysts and Veterinarians. R&W Communications, Dubai, United Arab Emirates, pp 509–513Google Scholar
  21. McKeever KH (1996) Erythropoietin: a new form of blood doping in horses. In: Auer D, Houghton E (eds) 11th International Conference of Racing Analysts and Veterinarians. Queensland, Australia, pp 79–84Google Scholar
  22. McKeever KH, Malinowski K, Christensen RA, Hafs HD (1998) Chronic recombinant equine somatotropin (eST) administration does not affect aerobic capacity or exercise performance in geriatric mares. Vet J 155:19–25CrossRefPubMedGoogle Scholar
  23. Norgren A, Ingvast-Larsson C, Kallings P, Fredriksson F, Bondesson U (2000) Contamination and urinary excretion of flunixin after repeated administration in the horse. In: Williams RB, Houghton E, Wade JF (eds) 13th International Conference of Racing Analysts and Veterinarians. R&W, Cambridge, UK, pp 377–380Google Scholar
  24. Pascoe JR, McCabe AE, Franti CE, Arthur RM (1985) Efficacy of furosemide in the treatment of exercise-induced pulmonary hemorrhage in thoroughbred racehorses. Am J Vet Res 46:2000–2003PubMedGoogle Scholar
  25. Piercy RJ, Swardson CJ, Hinchcliff KW (1998) Erythroid hypoplasia and anemia following administration of recombinant human erythropoietin to two horses. J Am Vet Med Assoc 212:244–247PubMedGoogle Scholar
  26. Popot MA, Houghton E, Ginn A, Jones M, Teale P, Samuels T, Lassourd V, Dunnett N, Cowan DA, Bonnaire Y, Toutain PL (1997) Cortisol concentrations in post competition horse urine: a French and British survey. Equine Vet J 29:226–229CrossRefPubMedGoogle Scholar
  27. Popot MA, Bobin S, Bonnaire Y, Monget P, Toquet MP, Fortier G, Delahaut P, Closset J (2000) Study related to the detection of recombinant equine growth hormone administration in the horse. In: Williams RB, Houghton WJF (eds) 13th International Conference of Racing Analysts and Veterinarians. Cambridge, UKGoogle Scholar
  28. Popot MA, Stojiljkovic N, Garcia P, Richard CA, Bonnaire Y, Tabet JC (2002) Additional studies on the detection of drugs in horse hair samples. In: Hill D, Hill W (eds) 14th International Conference of Racing Analysts and Veterinarians. R&W, Orlando, USA, pp 224Google Scholar
  29. Popot MA, Boyer S, Michel S, Garcia P, Bonnaire Y (2004) Approaches to the detection of drugs in horse faeces. In: Albert PH, Morton T, Wade JF (eds) 15th International Conference of Racing Analysts and Veterinarians. R&W Communications, Dubai, United Arab Emirates, pp 481Google Scholar
  30. Popot MA, Menaut L, Boyer S, Bonnaire Y, Toutain PL (2007) Spurious urine excretion drug profile in the horse due to bedding contamination and drug recycling: the case of meclofenamic acid. J Vet Pharmacol Ther 30:179–184CrossRefPubMedGoogle Scholar
  31. Singh AK, Gupta S, Barnes A, Carlson JM, Ayers JK (2007) Red blood cell erythropoietin, not plasma erythropoietin, concentrations correlate with changes in hematological indices in horses receiving a single dose of recombinant human erythropoietin by subcutaneous injection. J Vet Pharmacol Ther 30:175–178CrossRefPubMedGoogle Scholar
  32. Smith RL (2000) The zero tolerance approach to doping control in horseracing: a fading illusion? In: Williams RB, Houghton E, Wade JF (eds) 13th International Conference of Racing Analysts and Veterinarians. R&W, Cambridge, UK, pp 9–14Google Scholar
  33. Soma LR, Uboh CE (1998) Review of furosemide in horse racing: its effects and regulation. J Vet Pharmacol Ther 21:228–240CrossRefPubMedGoogle Scholar
  34. Spencer WA, Camargo FC, Karpiesiuk W, Hughes C, Stirling KH, Casey PJ, Tobin T (2008) Review of the current status of thresholds/withdrawal time guidelines for therapeutic medications in performance horses. AAEP Proc 54:29–37Google Scholar
  35. Sweeney CR, Soma LR (1984) Exercise-induced pulmonary hemorrhage in thoroughbred horses: response to furosemide or hesperidin-citrus bioflavinoids. J Am Vet Med Assoc 185:195–197PubMedGoogle Scholar
  36. Tay S, van Iren R, Coleman L, Auer D (1996) Evaluation of ELISA tests for erythropoietin (EPO) detection. In: 11th International Conference of Racing Analysts and Veterinarians. R&W, Queensland, Australia, pp 410–414Google Scholar
  37. Thevis M, Schanzer W (2007) Current role of LC-MS(/MS) in doping control. Anal Bioanal Chem 388:1351–1358CrossRefPubMedGoogle Scholar
  38. Thevis M, Kohler M, Schanzer W (2008) New drugs and methods of doping and manipulation. Drug Discov Today 13:59–66CrossRefPubMedGoogle Scholar
  39. Tobin T (1981) Drugs and the performance horse, 1st edn. Charles C Thomas, Springfield, USA pp 488Google Scholar
  40. Tobin T, Harkins JD, Lehner AF, Woods WE, Karpiesiuk W, Dirikolu L, Carter W, Boyles J, Sams RA (1998) An overview of analytical/pharmacological relationships and the need for limitations on the sensitivity of testing for certain agents. In: Laviolette B, Koupai-Abyazani (eds) Proceedings of the 12th International Conference of Racing Analysts and Veterinarians. R&W, Vancouver, British Columbia, Canada, pp 210–216Google Scholar
  41. Tobin T, Harkins JD, Sams RA (1999) Testing for therapeutic medications: analytical/pharmacological relationships and limitations’ on the sensitivity of testing for certain agents. J Vet Pharmacol Ther 22:220–233CrossRefPubMedGoogle Scholar
  42. Toutain PL (2009) How to extrapolate a withdrawal time from an EHLSC published detection time: a Monte Carlo simulation appraisal. Equine Vet J (in press)Google Scholar
  43. Toutain PL, Lassourd V (2002a) Pharmacokinetic/pharmacodynamic approach to assess irrelevant plasma or urine drug concentrations in postcompetition samples for drug control in the horse. Equine Vet J 34:242–249CrossRefPubMedGoogle Scholar
  44. Toutain PL, Lassourd V (2002b) Pharmacokinetics/pharmacodynamic assessment of irrelevant drug concentrations in horse plasma or urine for a selection of drugs. In: Hill D, Hill W (eds) 14th International Conference of Racing Analysts and Veterinarians. R&W, Orlando, Florida, USA, pp 19–27Google Scholar
  45. Van Eeno P, Delbeke FT (2003) Chromatographic and mass spectrometric criteria in doping and related areas. In: Schanzer W, Geyer H, Gotzmann A, Mareck U (eds) Recent advances in doping analysis. Sport and Buch Strauss, Köln, pp 149–159Google Scholar
  46. Wennerlund I, Ingvast-Larsson C, Kallings P, Fredriksson E, Bondesson U (2000) Pharmacokinetics and urinary excretion of naproxen after repeated oral administration. In: Williams RB, Houghton E, Wade JF (eds) 13th International Conference of Racing Analysts and Veterinarians. R&W, Cambridge, UK, pp 195–200Google Scholar
  47. Yamada M, Kinoshita K, Kurosawa M et al (2007) Analysis of exogenous nandrolone metabolite in horse urine by gas chromatography/combustion/carbon isotope ratio mass spectrometry. J Pharm Biomed Anal 45:654–658CrossRefPubMedGoogle Scholar
  48. Zawadzkas XA, Sides RH, Bayly WM (2006) Is improved high speed performance following furosemide administration due to diuresis-induced weight loss or reduced severity of exercise-induced pulmonary haemorrhage? Equine Vet J (Suppl 36):291–292PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.UMR181 Physiopathologie et Toxicologuie Experimentales INRA, ENVT, Ecole Nationale Vétérinaire de ToulouseToulouse cedex 03France

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