Pharmacodynamics and pharmacokinetics of tolfenamic acid in ruminating calves: Evaluation in models of acute inflammation

Injections of mild irritants intradermally (carrageenan, zymosan and dextran) and intracaveally (carrageenan) in a tissue cage model of inflammation were used in studies of the pharmacodynamics and pharmacokinetics of tolfenamic acid administered intramuscularly in calves. Inhibition of serum thromboxane (TS) B-2 and inflammatory exudate prostaglandin (PG)E-2 were used as indicators of the magnitude and time course of blockade of cyclo-oxygenase isoforms COX-1 and COX-2, respectively. Single doses of 2, 4 and 8mgkg(-1) tolfenamic acid partially inhibited irritant-induced rises in skin temperature (non-dose dependently) and skin oedema (dose-dependently). These doses also markedly inhibited serum TXB2 synthesis and the duration of inhibition was dose-related. A dose of 2mgkg(-1) tolfenamic acid also attenuated skin temperature rise over carrageenan-injected tissue cages, and markedly inhibited exudate PGE(2) synthesis, even though drug penetration into both exudate and tissue cage transudate was limited. Tolfenamic acid pharmacokinetics were characterized by a relatively short t(max) (0.94-2.04h), a high estimated Vdarea (1.79-3.20Lkg(-1)), an estimated t(1/2 beta) of 8.01-13.50h and Cl-beta of 0.142-0.175 Lkg(-1)h(-1). The actions of tolfenamic acid in inhibiting PGE(2) synthesis and in attenuating two of the cardinal signs of inflammation (heal and swelling) suggest that a dosage of 2mgkg(-1) administered intramuscularly should be effective clinically as an anti-inflammatory agent.