History dependence of force production in skeletal muscle: a proposal for mechanisms

Leukotrienes, products of the 5-lipoxygenase pathway of arachidonic acid metabolism, possess properties consistent with their involvement in a range of inflammatory diseases. In this study the pharmacokinetics and pharmacodynamics of the selective 5-lipoxygenase inhibitor, fenleuton, have been examined in the horse. Orally administered fenleuton (four 5 mg kg(-1) doses, given once daily) was absorbed from the gastrointestinal tract, and penetrated readily into tissue cage exudate, the ratio of the plasma:exudate AUC0-48h being 0.90+/-0.02 (n=6). Ionophore-stimulated leukotriene (LT) B4 synthesis, measured ex vivo in whole blood as immunoreactive LTB4, was significantly (P<0.05) inhibited throughout the 48 hour sampling period. Low levels of immunoreactive LTB4 were detected in transudate and these did not increase following addition of carrageenan to the tissue cages. Fenleuton had no significant inhibitory effect on exudate LTB4 concentrations. A reduction in carrageenan-induced skin swelling occurred, although this did not achieve statistical significance. The results obtained in this study suggest that fenleuton could be used to examine the role of LTs in inflammatory diseases of the horse.