Biotransformations of glafenine in the rat and in man.

The biotransformations of a therapeutic dose of the non-narcotic analgesic, glafenine, have been studied in the rat and in man. In the rat, the ester bond is extensively hydrolysed to give glafenic acid which is the major metabolite excreted in bile and in urine. Two minor pathways have been identified one leading by hydroxylation of the benzene ring of glafenine or glafenic acid in para of the amino-substituent to the corresponding phenols, the other, by oxidation of the quinoline nitrogen of glafenic acid, to its N-oxide. In vivo this N-oxide is partly reduced into the parent compound. Hydroxyglafenic acid is the product of both direct oxidation of glafenic acid and hydrolysis of hydroxyglafenine. The glyceric esters are conjugated as glucuro-ethers and/or sulfo-esters and the carboxylic metabolites as acyl glucuronides. The conjugation rate, high for glafenine, its phenol homologue and glafenic acid, is low for hydroxyglafenic acid and the N-oxide. The analogous urinary excretion patterns in man and in the rat suggest a similarity in the biotransformation of glafenine in these two species.

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.

Species differences in the biotransformation of 4-(2-methyl-3-(4-chlorobenzoyl)phenyl)butanoic acid (RU 16029).

1. 4-(2-Methyl-3-(4-chlorobenzoyl)phenyl)butanoic acid (RU 16029) is a potent anti-inflammatory and analgesic agent. In humans, its ketone group is rapidly reduced to an alcohol, whereas in rats, mice and dogs, its butanoic side-chain is rapidly oxidized to the corresponding acetic acid. 2. The extent of this oxidation was studied in eleven species. Cats, dogs, rabbits, hens and rodents readily oxidized the side-chain; humans, baboons and pigs showed only weak oxidizing capacity. 3. Species differences were also recorded in the secondary biotransformations. The acetic metabolite is excreted as an acylglucuronide in humans and rats, but as an amide-like conjugate in mice. 4. Comparison with biotransformations undergone by structurally related compounds confirms that the metabolism of a new compound in different species is unpredictable.