• 1. Modric S, Martinez M. Patient variation in veterinary medicine—part II—influence of physiological variables. J Vet Pharmacol Ther 2011;34:209223.

    • Search Google Scholar
    • Export Citation
  • 2. Nouws JF. Pharmacokinetics in immature animals: a review. J Anim Sci 1992;70:36273634.

  • 3. Igarza L, Soraci A, Auza N, et al. Some pharmacokinetic parameters of R-(−)- and S-(+)-ketoprofen: the influence of age and differing physiological status in dairy cattle. Vet Res Commun 2004;28:8187.

    • Search Google Scholar
    • Export Citation
  • 4. Igarza L, Soraci A, Auza N, et al. Pharmacokinetic parameters of (R)-(−) and (S)-(+)-flurbiprofen in dairy bovines. Vet Res Commun 2006;30:513522.

    • Search Google Scholar
    • Export Citation
  • 5. Volner Z, Nouws JF, Kozjek F, et al. Age-dependent pharmacokinetics of phenylbutazone in calves. Vet Q 1990;12:98102.

  • 6. Barnett SC, Sischo WM, Moore DA, et al. Evaluation of flunixin meglumine as an adjunct treatment for diarrhea in dairy calves. J Am Vet Med Assoc 2003;223:13291333.

    • Search Google Scholar
    • Export Citation
  • 7. Kleinhenz MD, Van Engen NK, Gorden PJ, et al. The pharmacokinetics of transdermal flunixin meglumine in Holstein calves. J Vet Pharmacol Ther 2016;39: 612615.

    • Search Google Scholar
    • Export Citation
  • 8. Julious SA, Debarnot CA. Why are pharmacokinetic data summarized by arithmetic means? J Biopharm Stat 2000;10:5571.

  • 9. Fraccaro E, Coetzee JF, Odore R, et al. A study to compare circulating flunixin, meloxicam and gabapentin concentrations with prostaglandin E@@sb@@2@@/sb@@ levels in calves undergoing dehorning. Res Vet Sci 2013;95:204211.

    • Search Google Scholar
    • Export Citation
  • 10. Stock ML, Barth LA, Van Engen NK, et al. Impact of carprofen administration on stress and nociception responses of calves to cautery dehorning. J Anim Sci 2016;94:542555.

    • Search Google Scholar
    • Export Citation
  • 11. Kissell LW, Brinson PD, Gehring R, et al. Pharmacokinetics and tissue elimination of flunixin in veal calves. Am J Vet Res 2016;77:634640.

    • Search Google Scholar
    • Export Citation
  • 12. Delatour P, Foot R, Foster AP, et al. Pharmacodynamics and chiral pharmacokinetics of carprofen in calves. Br Vet J 1996;152:183198.

  • 13. Jensen RC, Fischer JH, Cwik MJ. Effect of age and training status on pharmacokinetics of flunixin meglumine in Thoroughbreds. Am J Vet Res 1990;51:591594.

    • Search Google Scholar
    • Export Citation
  • 14. Brown SA, Chester ST, Robb EJ. Effects of age on the pharmacokinetics of single dose ceftiofur sodium administered intramuscularly or intravenously to cattle. J Vet Pharmacol Ther 1996;19:3238.

    • Search Google Scholar
    • Export Citation
  • 15. Miciletta M, Cuniberti B, Barbero R, et al. In vitro enantioselective pharmacodynamics of carprofen and flunixin-meglumine in feedlot cattle. J Vet Pharmacol Ther 2014;37:4352.

    • Search Google Scholar
    • Export Citation
  • 16. Donalisio C, Barbero R, Cuniberti B, et al. Effects of flunixin meglumine and ketoprofen on mediator production in ex vivo and in vitro models of inflammation in healthy dairy cows. J Vet Pharmacol Ther 2013;36:130139.

    • Search Google Scholar
    • Export Citation

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Effect of age on the pharmacokinetics and pharmacodynamics of flunixin meglumine following intravenous and transdermal administration to Holstein calves

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  • 1 Department of Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA 50011.
  • | 2 Department of Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA 50011.
  • | 3 Department of Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA 50011.
  • | 4 Department of Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA 50011.
  • | 5 Department of Anatomy and Physiology and Institute for Computational Comparative Medicine, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.
  • | 6 Pharmacology Analytical Support Team, College of Veterinary Medicine, Iowa State University, Ames, IA 50011.
  • | 7 Orchard Veterinary Centre, 59 Loughgall Rd, Armagh BT61 7NG, Northern Ireland.
  • | 8 Castle Veterinary Surgeons, Montalbo Rd, Barnard Castle, DL12 8ED, England.
  • | 9 Department of Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA 50011.
  • | 10 Pharmacology Analytical Support Team, College of Veterinary Medicine, Iowa State University, Ames, IA 50011.

Abstract

OBJECTIVE To determine the effect of age on the pharmacokinetics and pharmacodynamics of flunixin meglumine following IV and transdermal administration to calves.

ANIMALS 8 healthy weaned Holstein bull calves.

PROCEDURES At 2 months of age, all calves received an injectable solution of flunixin (2.2 mg/kg, IV); then, after a 10-day washout period, calves received a topical formulation of flunixin (3.33 mg/kg, transdermally). Blood samples were collected at predetermined times before and for 48 and 72 hours, respectively, after IV and transdermal administration. At 8 months of age, the experimental protocol was repeated except calves received flunixin by the transdermal route first. Plasma flunixin concentrations were determined by liquid chromatography-tandem mass spectroscopy. For each administration route, pharmacokinetic parameters were determined by noncompartmental methods and compared between the 2 ages. Plasma prostaglandin (PG) E2 concentration was determined with an ELISA. The effect of age on the percentage change in PGE2 concentration was assessed with repeated-measures analysis. The half maximal inhibitory concentration of flunixin on PGE2 concentration was determined by nonlinear regression.

RESULTS Following IV administration, the mean half-life, area under the plasma concentration-time curve, and residence time were lower and the mean clearance was higher for calves at 8 months of age than at 2 months of age. Following transdermal administration, the mean maximum plasma drug concentration was lower and the mean absorption time and residence time were higher for calves at 8 months of age than at 2 months of age. The half maximal inhibitory concentration of flunixin on PGE2 concentration at 8 months of age was significantly higher than at 2 months of age. Age was not associated with the percentage change in PGE2 concentration following IV or transdermal flunixin administration.

CONCLUSIONS AND CLINICAL RELEVANCE In calves, the clearance of flunixin at 2 months of age was slower than that at 8 months of age following IV administration. Flunixin administration to calves may require age-related adjustments to the dose and dosing interval and an extended withdrawal interval.

Abstract

OBJECTIVE To determine the effect of age on the pharmacokinetics and pharmacodynamics of flunixin meglumine following IV and transdermal administration to calves.

ANIMALS 8 healthy weaned Holstein bull calves.

PROCEDURES At 2 months of age, all calves received an injectable solution of flunixin (2.2 mg/kg, IV); then, after a 10-day washout period, calves received a topical formulation of flunixin (3.33 mg/kg, transdermally). Blood samples were collected at predetermined times before and for 48 and 72 hours, respectively, after IV and transdermal administration. At 8 months of age, the experimental protocol was repeated except calves received flunixin by the transdermal route first. Plasma flunixin concentrations were determined by liquid chromatography-tandem mass spectroscopy. For each administration route, pharmacokinetic parameters were determined by noncompartmental methods and compared between the 2 ages. Plasma prostaglandin (PG) E2 concentration was determined with an ELISA. The effect of age on the percentage change in PGE2 concentration was assessed with repeated-measures analysis. The half maximal inhibitory concentration of flunixin on PGE2 concentration was determined by nonlinear regression.

RESULTS Following IV administration, the mean half-life, area under the plasma concentration-time curve, and residence time were lower and the mean clearance was higher for calves at 8 months of age than at 2 months of age. Following transdermal administration, the mean maximum plasma drug concentration was lower and the mean absorption time and residence time were higher for calves at 8 months of age than at 2 months of age. The half maximal inhibitory concentration of flunixin on PGE2 concentration at 8 months of age was significantly higher than at 2 months of age. Age was not associated with the percentage change in PGE2 concentration following IV or transdermal flunixin administration.

CONCLUSIONS AND CLINICAL RELEVANCE In calves, the clearance of flunixin at 2 months of age was slower than that at 8 months of age following IV administration. Flunixin administration to calves may require age-related adjustments to the dose and dosing interval and an extended withdrawal interval.

Contributor Notes

Dr. Kleinhenz's present address is Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

Dr. Van Engen's present address is Johnson Research LLC, 24007 US-20, Parma, ID 83660.

Dr. Coetzee's present address is Department of Anatomy and Physiology and Institute for Computational Comparative Medicine, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

Address correspondence to Dr. Coetzee (jcoetzee@vet.k-state.edu).