Species Differences in Pharmacokinetics and Pharmacodynamics

  • Pierre-Louis ToutainEmail author
  • Aude Ferran
  • Alain Bousquet-Mélou
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 199)


Veterinary medicine faces the unique challenge of having to treat many types of domestic animal species, including mammals, birds, and fishes. Moreover, these species have evolved into genetically unique breeds having certain distinguishable characteristics developed by artificial selection. The main challenge for veterinarians is not to select a drug but to determine, for the selected agent, a rational dosing regimen because the dosage regimen for a drug in a given species may depend on its anatomy, biochemistry, physiology, and behaviour as well as on the nature and causes of the condition requiring treatment. Both between- and within-species differences in drug response can be explained either by variations in drug pharmacokinetics (PK) or drug pharmacodynamics (PD), the magnitude of which varies from drug to drug. This chapter highlights selected aspects of species differences in PK and PD and considers underlying physiological and patho-physiological mechanisms in the main domestic species. Particular attention was paid to aspects of animal behaviour (food behaviour, social behavior, etc.) as a determinant of interspecies differences in PK or/and PD. Modalities of drug administration are many and result not only from anatomical, physiological and/or behavioural differences across species but also from management options. The latter is the case for collective/group treatment of food-producing animals, frequently dosed by the oral route at a herd or flock level. After drug administration, the main causes of observed inter-species differences arise from species differences in the handling of drugs (absorption, distribution, metabolism, and elimination). Such differences are most common and of greatest magnitude when functions which are phylogenetically divergent between species, such as digestive functions (ruminant vs. non-ruminant, carnivore vs. herbivore, etc.), are involved in drug absorption. Interspecies differences also exist in drug action but these are generally more limited, except when a particular targeted function has evolved, as is the case for reproductive physiology (mammals vs. birds vs. fishes; annual vs. seasonal reproductive cycle in mammals; etc.). In contrast, for antimicrobial and antiparasitic drugs, interspecies differences are more limited and rather reflect those of the pathogens than of the host. Interspecies difference in drug metabolism is a major factor accounting for species differences in PK and also in PD (production or not of active metabolites). Recent and future advances in molecular biology and pharmacogenetics will enable a more comprehensive view of interspecies differences and also between breeds with existing polymorphism. Finally, the main message of this review is that differences between species are not only numerous but also often unpredictable so that no generalisations are possible, even though for several drugs allometric approaches do allow some valuable interspecies extrapolations. Instead, each drug must be investigated on a species-by-species basis to guarantee its effective and safe use, thus ensuring the well-being of animals and safeguarding of the environment and human consumption of animal products.


Pharmacokinetics Pharmacodynamics Species variation Drug administration Drug disposition 


  1. Anil SS, Anil L, Deen J (2002) Challenges of pain assessment in domestic animals. J Am Vet Med Assoc 220:313–319CrossRefPubMedGoogle Scholar
  2. Ashley FH, Waterman-Pearson AE, Whay HR (2005) Behavioural assessment of pain in horses and donkeys: application to clinical practice and future studies. Equine Vet J 37:565–575CrossRefPubMedGoogle Scholar
  3. 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
  4. Baggot JD (1977) Principles of drug disposition in domestic animals: the basis of veterinary clinical pharmacology. WB Saunders Company, PhiladelphiaGoogle Scholar
  5. Baggot JD (2001) The physiological basis of veterinary clinical pharmacology. Blackwell, OxfordCrossRefGoogle Scholar
  6. Baggot JD, Brown SA (1998) Basis for selection of the dosage form. In: Hardee GE, Baggot JD (eds) Development and formulation of veterinary dosage forms. Marcel Dekker, New York, NY, pp 7–143Google Scholar
  7. Baverud V, Franklin A, Gunnarsson A, Gustafsson A, Hellander-Edman A (1998) Clostridium difficile associated with acute colitis in mares when their foals are treated with erythromycin and rifampicin for Rhodococcus equi pneumonia. Equine Vet J 30:482–488CrossRefPubMedGoogle Scholar
  8. Bogaards A, Jongen AJL, Dekker E, van den Akker JHTM, Sterenborg HJCM (2000) Design and performance of a real-time double ratio fluorescence imaging system for the detection of early cancers. Optical Biopsy III 1:2–8 268Google Scholar
  9. Bousquet-Mélou A, Mercadier S, Alvinerie M, Toutain PL (2004) Endectocide exchanges between grazing cattle after pour-on administration of doramectin, ivermectin and moxidectin. Int J Parasitol 34:1299–1307CrossRefPubMedGoogle Scholar
  10. Bradshaw JW (2006) The evolutionary basis for the feeding behavior of domestic dogs (Canis familiaris) and cats (Felis catus). J Nutr 136:1927S–1931SPubMedGoogle Scholar
  11. Calabrese EJ (1983) Principles of animal extrapolation. Wiley, New YorkGoogle Scholar
  12. Chiou WL, Jeong HY, Chung SM, Wu TC (2000) Evaluation of using dog as an animal model to study the fraction of oral dose absorbed of 43 drugs in humans. Pharm Res 17:135–140CrossRefPubMedGoogle Scholar
  13. Corrier DE, Byrd JA, Hargis BM, Hume ME, Bailey RH, Stanker LH (1999) Presence of Salmonella in the crop and ceca of broiler chickens before and after preslaughter feed withdrawal. Poult Sci 78:45–49PubMedGoogle Scholar
  14. Cortright KA, Craigmill AL (2006) Cytochrome P450-dependent metabolism of midazolam in hepatic microsomes from chickens, turkeys, pheasant and bobwhite quail. J Vet Pharmacol Ther 29:469–476CrossRefPubMedGoogle Scholar
  15. Court MH, Hay-Kraus BL, Hill DW, Kind AJ, Greenblatt DJ (1999) Propofol hydroxylation by dog liver microsomes: assay development and dog breed differences. Drug Metab Dispos 27:1293–1299PubMedGoogle Scholar
  16. Craigmill A (2003) A physiologically based pharmacokinetic model for oxytetracycline residues in sheep. J Vet Pharmacol Ther 26:55–63CrossRefPubMedGoogle Scholar
  17. Cribb A (2003) Metabolism: the cytochrome P450s of the dog. In: Whittem T (ed) 13th Biennial Symposium of the American Academy of Veterinary Pharmacology and Therapeutics. Charlotte, NC, USA, pp 30–34Google Scholar
  18. del Castillo JRE (2006) Population pharmacokinetic variability of feed-administered doxycycline in swine herds with and without paracetamol. In: 19th International Pig Veterinary Congress, Copenhagen, DenmarkGoogle Scholar
  19. FAO (2000) World watch list for domestic animal diversity, 3rd edn. UNEP FAO, Rome, ItalyGoogle Scholar
  20. Ferran AA, Kesteman AS, Toutain PL, Bousquet-Melou A (2009) Pharmacokinetic/pharmacodynamic analysis of the influence of inoculum size on the selection of resistance in Escherichia coli by quinolone in a mouse-thigh bacterial infection model. Antimicrob Agents Chemother 53:3384–3390CrossRefPubMedGoogle Scholar
  21. Fink-Gremmels J (2008) Implications of hepatic cytochrome P450-related biotransformation processes in veterinary sciences. Eur J Pharmacol 585:502–509CrossRefPubMedGoogle Scholar
  22. Fleischer S, Sharkey M, Mealey K, Ostrander EA, Martinez M (2008) Pharmacogenetic and metabolic differences between dog breeds: their impact on canine medicine and the use of the dog as a preclinical animal model. AAPS J 10:110–119CrossRefPubMedGoogle Scholar
  23. Garcia-Villar R, Toutain PL, Alvinerie M, Ruckebusch Y (1981) The pharmacokinetics of xylazine hydrochloride: an interspecific study. J Vet Pharmacol Ther 4:87–92CrossRefPubMedGoogle Scholar
  24. Gayrard V, Alvinerie M, Toutain PL (1999) Comparison of pharmacokinetic profiles of doramectin and ivermectin pour-on formulations in cattle. Vet Parasitol 81:47–55CrossRefPubMedGoogle Scholar
  25. Gioiosa L, Chiarotti F, Alleva E, Laviola G (2009) A trouble shared is a trouble halved: social context and status affect pain in mouse dyads. PLoS ONE 4:e4143CrossRefPubMedGoogle Scholar
  26. Glasser A, Murphy CJ, Troilo D, Howland HC (1995) The mechanism of lenticular accommodation in chicks. Vision Res 35:1525–1540CrossRefPubMedGoogle Scholar
  27. Gokbulut C, Karademir U, Boyacioglu M, McKellar QA (2008) The effect of sesame and sunflower oils on the plasma disposition of ivermectin in goats. J Vet Pharmacol Ther 31:472–478CrossRefPubMedGoogle Scholar
  28. Gonzalez A, Sahagun AM, Diez MJ, Fernandez N, Sierra M, Garcia JJ (2006) Pharmacokinetics of a novel formulation of ivermectin after administration to goats. Am J Vet Res 67:323–328CrossRefPubMedGoogle Scholar
  29. Guillot P, Sanders P, Mourot D (1988) Pharmacokinetic study of chloramphenicol in the rabbit. Ann Rech Vet 19:27–33PubMedGoogle Scholar
  30. Hansen BD (2003) Assessment of pain in dogs: veterinary clinical studies. ILAR J 44:197–205PubMedGoogle Scholar
  31. Houston T, Chay S, Woods WE, Combs G, Kamerling S, Blake JW, Edmundson AG, Vessiney R, Tobin T (1985) Phenylbutazone and its metabolites in plasma and urine of thoroughbred horses: population distributions and effects of urinary pH. J Vet Pharmacol Ther 8:136–149CrossRefPubMedGoogle Scholar
  32. Hunter RP (2009) Zoological pharmacology. In: Riviere JE, Papich MG (eds) Veterinary pharmacology and therapeutics, 9th edn. Wiley-Blackwell, Ames, IA, pp 1343–1352Google Scholar
  33. Hunter RP, Mahmood I, Martinez MN (2008) Prediction of xenobiotic clearance in avian species using mammalian or avian data: how accurate is the prediction? J Vet Pharmacol Ther 31:281–284CrossRefPubMedGoogle Scholar
  34. Ingebrigtsen K (1991) Factors affecting drug disposition in fish. In: Friis C, Gyrd-Hansen NP, Rsamussen F (eds) 5th congress of the European Association for Veterinary Pharmacology and Toxicology. Copenhagen, Denmark, pp 44–56Google Scholar
  35. KuKanich B, Coetzee JF, Gehring R, Hubin M (2007) Comparative disposition of pharmacologic markers for cytochrome P-450 mediated metabolism, glomerular filtration rate, and extracellular and total body fluid volume of Greyhound and Beagle dogs. J Vet Pharmacol Ther 30:314–319CrossRefPubMedGoogle Scholar
  36. Laffont CM, Alvinerie M, Bousquet-Mélou A, Toutain PL (2001) Licking behaviour and environmental contamination arising from pour-on ivermectin for cattle. Int J Parasitol 31:1687–1692CrossRefPubMedGoogle Scholar
  37. Langford DJ, Crager SE, Shehzad Z, Smith SB, Sotocinal SG, Levenstadt JS, Chanda ML, Levitin DJ, Mogil JS (2006) Social modulation of pain as evidence for empathy in mice. Science 312:1967–1970CrossRefPubMedGoogle Scholar
  38. Lees P (2009) Analgesic, antiinflammatory, antipyretic drugs. In: Riviere JE, Papich MG (eds) Veterinary pharmacology and therapeutics, 9th edn. Wiley-Blackwell, Ames, IA, pp 457–492Google Scholar
  39. Lees P, Taylor JBO, Higgins AJ, Sharma SC (1986) Phenylbutazone and oxyphenbutazone distribution into tissue fluids in the horse. J Vet Pharmacol Ther 9:204–212CrossRefPubMedGoogle Scholar
  40. Lees P, Taylor JBO, Higgins AJ, Sharma SC (1988) In vitro and in vivo studies on the binding of phenylbutazone and related drugs to equine feeds and digesta. Res Vet Sci 44:50–56PubMedGoogle Scholar
  41. Lees P, Concordet D, Shojaee Aliabadi F, Toutain PL (2006) Drug selection and optimisation of dosage schedules to minimize antimicrobial resistance. In: Aarestrup FM (ed) Antimicrobial resistance in bacteria of animal origin. ASM, Washington, DC, pp 49–71Google Scholar
  42. Lizarraga I, Sumano H, Brumbaugh GW (2004) Pharmacological and pharmacokinetic differences between donkeys and horses. Equine Vet Educ 16:102–112CrossRefGoogle Scholar
  43. Lu C, Li AP (2001) Species comparison in P450 induction: effects of dexamethasone, omeprazole, and rifampin on P450 isoforms 1A and 3A in primary cultured hepatocytes from man, Sprague-Dawley rat, minipig, and beagle dog. Chem Biol Interact 134:271–281CrossRefPubMedGoogle Scholar
  44. Maddison J (1999) Owner compliance with drug treatment regimens. J Small Anim Pract 40:348–348CrossRefPubMedGoogle Scholar
  45. Mahmood I (2005) Interspecies pharmacokinetic scaling allometric principles and applications. Pine House, Rockeville, MarylandGoogle Scholar
  46. Maitho TE, Lees P, Taylor JB (1986) Absorption and pharmacokinetics of phenylbutazone in Welsh Mountain ponies. J Vet Pharmacol Ther 9:26–39CrossRefPubMedGoogle Scholar
  47. Martinez M, Amidon G, Clarke L, Jones WW, Mitra A, Riviere J (2002) Applying the biopharmaceutics classification system to veterinary pharmaceutical products. Part II. Physiological considerations. Adv Drug Deliv Rev 54:825–850CrossRefPubMedGoogle Scholar
  48. Martinsen B, Horsberg TE (1995) Comparative single-dose pharmacokinetics of four quinolones, oxolinic acid, flumequine, sarafloxacin, and enrofloxacin, in Atlantic salmon (Salmo salar) held in seawater at 10°C. Antimicrob Agents Chemother 39:1059–1064PubMedGoogle Scholar
  49. Martinsen B, Oppegaard H, Wichstrom R, Myhr E (1992) Temperature-dependent in vitro antimicrobial activity of four 4-quinolones and oxytetracycline against bacteria pathogenic to fish. Antimicrob Agents Chemother 36:1738–1743PubMedGoogle Scholar
  50. Mealey KL (2009) Pharmacogenomics. In: Riviere JE, Papich MG (eds) Veterinary pharmacology and therapeutics, 9th edn. Wiley-Blackwell, Ames, IAGoogle Scholar
  51. Monshouwer M, van’t Klooster GAE, Nijmeijer SM, Witkamp RF, van Miert ASJPAM (1998) Characterization of cytochrome P450 isoenzymes in primary cultures of pig hepatocytes. Toxicology in Vitro 12:715–723CrossRefPubMedGoogle Scholar
  52. Nebbia C, Ceppa L, Dacasto M, Nachtmann C, Carletti M (2001) Oxidative monensin metabolism and cytochrome P450 3A content and functions in liver microsomes from horses, pigs, broiler chicks, cattle and rats. J Vet Pharmacol Ther 24:399–403CrossRefPubMedGoogle Scholar
  53. Norgren A, Ingvast-Larsson C, Kallings P, Fredriksson E, Bondesson U (2000) Contamination and urinary 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
  54. Oaks JL, Gilbert M, Virani MZ, Watson RT, Meteyer CU, Rideout BA, Shivaprasad HL, Ahmed S, Chaudhry MJ, Arshad M, Mahmood S, Ali A, Khan AA (2004) Diclofenac residues as the cause of vulture population decline in Pakistan. Nature 427:630–633CrossRefPubMedGoogle Scholar
  55. Paulson SK, Engel L, Reitz B, Bolten S, Burton EG, Maziasz TJ, Yan B, Schoenhard GL (1999) Evidence for polymorphism in the canine metabolism of the cyclooxygenase 2 inhibitor, celecoxib. Drug Metab Dispos 27:1133–1142PubMedGoogle Scholar
  56. Pilar G, Nunez R, Mclennan IS et al (1987) Muscarinic and nicotinic synaptic activation of the developing chicken iris. J Neurosci 7:3813–3826PubMedGoogle Scholar
  57. 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
  58. Prichard RK, Hennessy DR (1981) Effect of esophageal groove closure on the pharmacokinetic behavior and efficacy of oxfendazole in sheep. Res Vet Sci 30:22–27PubMedGoogle Scholar
  59. Rathbone MJ, Witchey-Lakshmanan L (2000) Veterinary drug delivery Part III – Preface. Adv Drug Deliv Rev 43:1CrossRefGoogle Scholar
  60. Reimschuessel R, Stewart L, Squibb E, Hirokawa K, Brady T, Brooks D, Shaikh B, Hodsdon C (2005) Fish drug analysis–Phish-Pharm: a searchable database of pharmacokinetics data in fish. AAPS J 7:E288–E327CrossRefPubMedGoogle Scholar
  61. Riviere JE, Martin-Jimenez T, Sundlof SF, Craigmill AL (1997) Interspecies allometric analysis of the comparative pharmacokinetics of 44 drugs across veterinary and laboratory animal species. J Vet Pharmacol Ther 20:453–463CrossRefPubMedGoogle Scholar
  62. Sakuma T, Shimojima T, Miwa K, Kamataki T (2004) Cloning CYP2D21 and CYP3A22 cDNAs from liver of miniature pigs. Drug Metab Dispos 32:376–378CrossRefPubMedGoogle Scholar
  63. Sangster NC, Rickard JM, Hennessy DR, Steel JW, Collins GH (1991) Disposition of oxfendazole in goats and efficacy compared with sheep. Res Vet Sci 51:258–263PubMedGoogle Scholar
  64. Sarasola P, Jernigan AD, Walker DK, Castledine J, Smith DG, Rowan TG (2002) Pharmacokinetics of selamectin following intravenous, oral and topical administration in cats and dogs. J Vet Pharmacol Ther 25:265–272CrossRefPubMedGoogle Scholar
  65. Sargison ND, Stafford KJ, West DM (1999) Fluoroscopic studies of the stimulatory effects of copper sulphate and cobalt sulphate on the oesophageal groove of sheep. Small Rumin Res 32:61–67CrossRefGoogle Scholar
  66. Scott EW, Kinabo LD, McKellar QA (1990) Pharmacokinetics of ivermectin after oral or percutaneous administration to adult milking goats. J Vet Pharmacol Ther 13:432–435CrossRefPubMedGoogle Scholar
  67. Séguin B (2002) Feline injection site sarcomas. Veterinary Clinics of North America-Small Animal Practice 32:983–995CrossRefGoogle Scholar
  68. Shao ZJ (2001) Aquaculture pharmaceuticals and biologicals: current perspectives and future possibilities. Adv Drug Deliv Rev 50:229–243CrossRefPubMedGoogle Scholar
  69. Soave O, Brand CD (1991) Coprophagy in animals: a review. Cornell Vet 81:357–364PubMedGoogle Scholar
  70. Sutton SC (2004) Companion animal physiology and dosage form performance. Adv Drug Deliv Rev 56:1383–1398CrossRefPubMedGoogle Scholar
  71. Thombre AG (2004) Oral delivery of medications to companion animals: palatability considerations. Adv Drug Deliv Rev 56:1399–1413CrossRefPubMedGoogle Scholar
  72. Toutain PL (2009) Pharmacokinetics/pharmacodynamics integration in dosage regimen optimization for veterinary medicine. In: Riviere JE, Papich M (eds) Veterinary pharmacology and therapeutics, 9th edn. Wiley-Blackwell, Ames, IAGoogle Scholar
  73. Vaclavikova R, Soucek P, Svobodova L, Anzenbacher P, Simek P, Guengerich FP, Gut I (2004) Different in vitro metabolism of paclitaxel and docetaxel in humans, rats, pigs, and minipigs. Drug Metab Dispos 32:666–674CrossRefPubMedGoogle Scholar
  74. Vandamme TF, Ellis KJ (2004) Issues and challenges in developing ruminal drug delivery systems. Adv Drug Deliv Rev 56:1415–1436CrossRefPubMedGoogle Scholar
  75. Vermeulen B, De Backer P, Remon JP (2002) Drug administration to poultry. Adv Drug Deliv Rev 54:795–803CrossRefPubMedGoogle Scholar
  76. Watkins JB, Smith GS, Hallford DM (1987) Characterization of xenobiotic biotransformation in hepatic, renal and gut tissues of cattle and sheep. J Anim Sci 65:186–195PubMedGoogle Scholar
  77. 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
  78. Wooldridge AA, Eades SC, Hosgood GL, Moore RM (2002) In vitro effects of oxytocin, acepromazine, detomidine, xylazine, butorphanol, terbutaline, isoproterenol, and dantrolene on smooth and skeletal muscles of the equine esophagus. Am J Vet Res 63:1732–1737CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • Pierre-Louis Toutain
    • 1
    Email author
  • Aude Ferran
    • 1
  • Alain Bousquet-Mélou
    • 1
  1. 1.Unité Mixte de Recherche 181 Physiopathologie et Toxicologie ExpérimentalesInstitut National de la Recherche Agronomique et Ecole Nationale Vétérinaire de ToulouseToulouse cedex 03France

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