Pharmacokinetics of the Anti-Inflammatory Tiaprofenic Acid in Humans, Mice, Rats, Rabbits, and Dogs

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The pharmacokinetics of tiaprofenic acid were studied in rats, dogs, mice, and rabbits using the 14C-labeled compound and in humans using the radioinert compound. Its absorption was partially gastric but mainly intestinal and was total in all species. Its apparent volume of distribution was small; it was bound markedly to albumin, and its plasma clearance was high in all species. Absence of retention was confirmed in rats by the very low tissue radioactivity levels 24 hr after oral dosing. In humans, identical maximum plasma concentrations and elimination rates were recorded after the first and 40th dose during a 2-week treatment with 200 mg three times daily. During this period, constant residual levels were recorded before the first dose of the day. These results indicate that, for a dose in the therapeutic range, a steady state was reached as early as the end of the 1st day of treatment and that tiaprofenic acid did not inhibit or induce its own biotransformation. Urinary excretion accounted for one-half of the dose in rats and from 0.6 to 0.9 in humans, dogs, mice, and rabbits. Two metabolites were formed, one resulting from the reduction of the ketone group to an alcohol and the other from oxidation generating a phenol in the benzene ring in the paro-position to the ketone group. These two metabolites were common to all species, but the latter was present in minute amounts only in dogs. Tiaprofenic acid was conjugated as an amide in dogs and as an acylglu- curonide in the other species. In rats, phenobarbital induced the oxidative, but not the reductive, pathway.