Emetic Liability Testing in Ferrets

Mark A. Osinski1, Terese R. Seifert1, Thomas K. Shaughnessy1, Gary A. Gintant1, Bryan F. Cox1

1 Abbott Laboratories, Abbott Park, Illinois
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 5.31
DOI:  10.1002/0471141755.ph0531s20
Online Posting Date:  May, 2003
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Abstract

Evidence of a candidate drug's efficacy and safety is mandatory for successful drug registration by regulatory authorities. However, a third property, tolerability, often determines a drug's acceptance by the patient population. Gastrointestinal events often determine the maximum tolerated dose in Phase I clinical trials. If the plasma concentrations achieved at the maximum tolerable dose are below those required for efficacy, the drug will certainly fail. The identification of a compound's emetic/nauseogenic liability early in the discovery process can be critical to the ultimate success of the drug discovery project. Ferrets are small carnivores (∼1 kg) of the Mustelidae family that vomit in response to many pharmacological classes of drugs as well as to cytotoxic chemotherapeutics and radiation. This unit describes a simple method for evaluating the emetic and nauseogenic potential of drug candidates in ferrets.

     
 
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Table of Contents

  • Commentary
  • Figures
  • Tables
     
 
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Materials

Basic Protocol 1:

  Materials
  • Descented, castrated male ferrets weighing ∼0.75 to 1.5 kg (Marshall Farms USA)
  • Test compounds in appropriate vehicle(s)
  • Polycarbonate animal cages, 48 × 27 × 20–cm (Nalgene Nunc), with wire lids; one for each animal
  • Feline stomach tube speculum (J.A. Webster)
  • Feeding tube (8‐French × 15‐in.; Kendall)
  • 3‐ml syringes (Becton Dickinson Labware)
  • 23‐G, 1‐in. hypodermic needles (Monoject, Sherwood Medical)
  • Stopwatches or digital timers (one for each animal)
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Figures

Videos

Literature Cited

Literature Cited
   Andrews, P.L.R., Davis, C.J., Grahame‐Smith, D.G., and Maskell, L.B. 1986. Apomorphine‐induced vomiting in the ferret; anomalies of response to dose and route of administration. Br. J. Pharmacol. 89:860P.
   Andrews, P.L.R., Davis, C.J., Bingham, S., Davidson, H.I.M., Hawthorn, J., and Maskell, L. 1990. The abdominal visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity. Can. J. Physiol. Pharmacol. 68:325‐345.
   Bermudez, J., Boyle, E.A., Miner, W.D., and Sanger, G.J. 1988. The anti‐emetic potential of the 5‐hydroxytryptamine3 receptor antagonist BRL 43694. Br. J. Cancer 58:644‐650.
   Borison, H.L. and Wang, S.C. 1953. Physiology and pharmacology of vomiting. Pharmacol. Rev. 5:193‐230.
   Brizzee, K.R. and Mehler, W.R. 1986. The central nervous connections involved in the vomiting reflex. In Nausea and Vomiting: Mechanisms and Treatment (C.J. Davis, G.V. Lake‐Bakaar, and D.G. Grahame‐Smith eds.) pp. 31‐55. Springer‐Verlag, Berlin.
   Costall, B., Naylor, R.J., Owera‐Atepo, J.B., and Tattersall, F.D. 1989. The responsiveness of the ferret to apomorphine induced emesis. Br. J. Pharmacol. 96:329P.
   Florczyk, A.P., Schurig, J.E., and Bradner, W.T. 1982. Cisplatin‐induced emesis in the ferret: A new animal model. Cancer Treat. Rep. 66:187‐189.
   Fox, J.G. 1998. Taxonomy, history, and use. In Biology and Diseases of the Ferret (J.G. Fox ed.) pp.3‐18. Lippincott Williams & Wilkins, Philadelphia.
   Gad, S.C. and Weil, C.S. 1988. Statistics and Experimental Design for Toxicologists. Telford Press, Caldwell, N.J.
   King, G.L. 1988. Characterization of radiation‐induced emesis in the ferret. Radiat. Res. 114:599‐612.
   King, G.L. 1990. Animal models in the study of vomiting. Can. J. Physiol. Pharmacol. 68:260‐268.
   Knox, A.P., Strominger, N.L., Battles, A.H., and Carpenter, D.O. 1993. Behavioral studies of emetic sensitivity in the ferret. Brain Res. Bull. 31:477‐484.
   Matsuki, N., Ueno, S., Kaji, T., Ishihara, A., Wang, C.H., and Saito, H. 1988. Emesis induced by cancer chemotherapeutic agents in the Suncus murinus: A new experimental model. Jpn. J. Pharmacol. 48:303‐306.
   Robichaud, A., Tattersall, F.D., Choudhury, I., and Rodger, I.W. 1999. Emesis induced by inhibitors of type IV cyclic nucleotide phosphodiesterase (PDE IV) in the ferret. Neuropharmacology 38:289‐297.
   Ueno, S., Matsuki, N., and Saito, H. 1987. Suncus murinus: A new experimental model in emesis research. Life Sci. 41:513‐518.
   Ueno, S., Matsuki, N., and Saito, H. 1988. Suncus murinus as a new experimental model for motion sickness. Life Sci. 43:413‐420.
   Yoshikawa, T., Yoshida, N., and Hosoki, K. 1996. Involvement of dopamine D3 receptors in the area postrema in R(+)‐7‐OH‐DPAT‐induced emesis in the ferret. Eur. J. Pharmacol. 301:143‐149.
   Zaman, S., Woods, A.J., Watson, J.W., Reynolds, D.J.M., and Andrews, P.L.R. 2000. The effect of the NK1 receptor antagonist CP‐99,994 on emesis and c‐fos protein induction by loperamide in the ferret. Neuropharmacology 39:316‐323.
Key References
   Andrews, et al., 1990. See above.
  Excellent overview on the use of ferrets in emesis research written by the preeminent researcher in the field. Detailed investigation into the role of the visceral afferent innervation in vomiting.
   Fox, J.G., 1998. See above.
  Comprehensive handbook on the use of ferrets in biomedical research. Chapters on gross and neuro‐anatomy, physiology, husbandry, normal clinical values, breeding, etc. Especially helpful for investigators unaccustomed to working with ferrets.
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