Scientific literature regarding the effects of age on the pharmacokinetics of drugs in cattle and other veterinary species is sparse. Cattle, in particular, undergo changes in body structure and composition as they mature from preruminant calves to adult ruminants. Those changes include alterations in total water composition, body surface area, and adipose tissue development; female ruminants also undergo changes associated with gestation and lactation.1 Changes in drug absorption, metabolism, and renal excretion as individuals mature are the basis for age-dependent differences in the pharmacokinetics of various drugs.2 In cattle, the effect of age on the pharmacokinetics of some NSAIDs has been investigated.3–5 However, there is a lack of information regarding the effect of age on the pharmacokinetics of flunixin meglumine (flunixin) in cattle.
Flunixin is a nicotinic acid derivative and is the only NSAID approved by the FDA for use in cattle in the United States. Injectable formulations of flunixin are labeled for the treatment of pyrexia associated with bovine respiratory disease and endotoxic mastitis and inflammation associated with endotoxemia in adult cattle. Flunixin has also been reported to be useful as an adjunctive treatment for neonatal calves with diarrhea.6
Because flunixin is an NSAID, it has direct effects on COX enzymes associated with inflammation. The COX pathway is responsible for the conversion of arachidonic acid to PGE2, PGI, PGF2α, and thromboxane. Cyclooxygenase has 2 isoforms, COX-1 and COX-2, and each isoform has distinct functions. The COX-1 isoform is constitutively produced in tissues and is associated with homeostasis. The COX-2 isoform is constitutively expressed in some tissues and can be markedly upregulated subsequent to inflammatory insults, tissue injury, or localized hypotension. Expression of COX-2 products such as PGE2 and PGI2 correlates best with the anti-inflammatory function of flunixin and other NSAIDs. For example, inhibition of PGE2 and PGI2 is positively correlated with anti-inflammatory activity, and an increase in PGE2 and PGI2 concentrations is associated with poor anti-inflammatory activity.
The objective of the study reported here was to investigate the effect of age on the pharmacokinetics and pharmacodynamics of flunixin following IV and transdermal administration to Holstein calves. We hypothesized that the pharmacokinetics and associated pharmacodynamics of flunixin would differ as calves age owing to changes in physiology, body composition, and growth.
Supported by the Pharmacology Analytical Support Team (PhAST) in the College of Veterinary Medicine, Iowa State University.
This manuscript represents a portion of a dissertation submitted by Dr. Kleinhenz to the Kansas State University Department of Veterinary Diagnostic and Production Animal Medicine as partial fulfillment of the requirements for a Doctor of Philosophy degree.
Certara provided Phoenix, a pharmacokinetics-pharmacodynamics modeling and simulation platform, for the Phoenix Center of Excellence within the Institute of Computational Comparative Medicine, College of Veterinary Medicine, Kansas State University.
Area under the plasma concentration-time curve
Plasma clearance rate
Maximum plasma concentration
Half maximal inhibitory concentration
Mean absorption time
Mean residence time
Volume of distribution at steady state after IV administration
Corid, Merial LLC, Duluth, Ga.
Banamine injectable solution, Merck Animal Health, Madison, NJ.
BD Vacutainer, Franklin Lakes, NJ.
Finadyne Transdermal Pour-On, MSD Animal Health, Dublin, Ireland.
Phenomenex, Torrance, Calif.
Phoenix 64, Certara, Princeton, NJ.
Sigma-Aldrich Corp, St Louis, Mo.
Cayman Chemicals, Ann Arbor, Mich.
Prism7, GraphPad Software Inc, La Jolla, Calif.
JMP Pro, version 12.0, SAS Institute Inc, Cary, NC.
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