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

AM Bendele, KJ Ruterbories, SM Spaethe, DN Benslay, TD Lindstrom, SJ Lee and RW Naismith

Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana.

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)

Volume 260, Issue 3, pp. 1194-1198, 03/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1992 by the American Society for Pharmacology and Experimental Therapeutics.