Pharmacokinetic study of a peripheral analgesic, floctafenin, in man, mouse, rat, and dog

The pharmacokinetics of floctafenin has been studied in man, mice, rats, and dogs at pharmacological doses. Its absorption, which is exclusively intestinal, is good in man and rodents, but only partial in dogs. Its high plasma clearance rate is primarily due to hepatic hydrolysis to floctafenic acid, which is the main circulating product almost immediately following hydrolysis to floctafenic acid, which is the main circulating product almost immediately following iv administration. The compound binds to two sets of binding sites in animal serum and human plasma with affinity constants of 10(7) M-1 and 10(5) M-1 at 4 degrees C in all species except the dog, where binding is weaker. This binding has been shown to be solely accounted for by albumin. Floctafenin, less protein-bound than floctafenic acid, diffuses more widely into tissues, but very low quantities of the ester and virtually negligible quantities of the acid cross the blood-brain barrier, indicating that their analgesic activity is exclusively peripheral. The elimination of floctafenin and its metabolites is practically complete in 24 hr. The main excretory route is via the bile, biliary excretion being largely predominant in dogs and rats, and somewhat less so in man and mice. There is no enterohepatic cycle of note. The main metabolite in both bile and urine is floctafenic acid. A secondary metabolic pathway, common to all species, leads, by hydroxylation in the postion para to the anthranilic nitrogen, to the corresponding phenols. All products in man and rats are excreted primarily in the form of ether and/or ester O-glucuronides.