Correlation of anti-inflammatory activity with peak tissue rather than peak plasma levels of BF389

BF389 (Biofor 389) is a potent anti-inflammatory agent in various animal models including adjuvant and type II collagen arthritis in rats. In vitro assays indicate that this compound is a mixed inhibitor of arachidonic acid metabolism. The compound was evaluated for effects on the acute inflammatory response in the carrageenan paw edema assay in rats using a standard protocol in which the animals were given single or multiple (daily for 5 days) p.o. doses of the compound. Carrageenan was injected into the footpad of each animal 1 hr after dosing and volumes of both hind paws were determined 3 hr later. Basal serum prostaglandin (PG) E2 levels and PGE2 levels in arachidonate-stimulated blood from these same animals also were measured. No anti-inflammatory activity was observed in BF389-treated rats despite the occurrence of profound suppression of basal and stimulated PGE2 production. Animals treated with conventional nonsteroidal anti-inflammatory drugs in this assay had both suppressed PGE2 production and significant anti-inflammatory activity. In another study, groups of rats were given p.o. doses of 1, 10, 100 or 250 mg/kg of BF389 for 5 days in order to determine peak concentrations, T1/2s and total areas under the plasma (tissue) drug concentration curves in plasma and paws. Peak plasma concentrations occurred 2 to 4 hr postdosing and the half-life was 8 to 15 hr over the 1- to 250-mg/kg/day dose range. Peak paw concentrations occurred 6 to 12 hr postdosing and the levels were 9- to 14-fold greater in the paw than in the plasma.(ABSTRACT TRUNCATED AT 250 WORDS)