The comparative absorption, distribution, metabolism, and excretion of naproxen [( +)-6-methoxy-cu-methyl-2-naphthaleneacetic acid], a potent systemic anti-inflammatory agent, was studied in several species including man. Blood, urine, and fecal analyses were performed on specimens collected at several times after either oral ingestion or rapid intravenous administration of a radioactive dose. Naproxen was found to be rapidly absorbed in all species and, once in the blood, was eliminated with half-lives ranging from 2 to 35 hr. The human plasma half-life ranged from 10 to 17 hr. Evaluation of the distribution of radioactivity in various tissues and organs of the rat indicated that no unusual amount was retained in the animal 24 hr. after administration, nor did there seem to be preferential localization. Estimated volumes of distribution indicated that a large fraction of the drug is held in the blood, much like salicylates are. Virtually all of the drug present in the blood of humans was determined to be unchanged naproxen, while the rat and the monkey showed minor amounts of transformation products. With the exception of the dog, all species excreted naproxen and its metabolic transformation products predominantly in the urine. In the dog the preferred route was fecal. In the human, 94% of the intravenously administered radioactivity appeared in the urine after 5 days, while I-2% appeared in the feces. Following 14 days of continuous exposure to the drug, the three human subjects displayed no evidence of induction of metabolizing enzymes.
Keyphrases 0 Naproxen-absorption, distribution, metabolism, and excretion in animals, man (+)-QMethoxy-~~-methyl-2naphthaleneacetic acid-absorption, distribution, metabolism, and excretion in animals, man 0 Metabolism-naproxen, animals, man
The chemistry of naproxen [(+)-6-methoxy-a-methyl-2-naphthaleneacetic acid1], a potent systemic anti-inflammatory agent, was reported by Harrison et al. . Rooks (2) described its biological activities. Naproxen was found to be 0.7, 5.5, and 11 times as active as indomethacin, aspirin, and phenylbutazone, respectively, in inhibiting the carrageenin-induced inflammation of the rat paw. Its analgesic activity was found to be approximately 7 times that of aspirin in a phenylquinone-induced writhing assay, and a dose-related antipyretic activity was observed in rats with yeast-induced pyresis. No significant cardiovascular or CNS activity was noticed. This report summarizes results of a comparative study of the absorption, distribution, metabolism, and excretion of naproxen in several species including man.
Methods
The tritiated naproxen2 was prepared by the Javorsky and Gorin (3) exchange method with isotopic water. Proof of structure was 1 This name is the correct Chemical Abstracts index name, but this compound was identified previously in the chemical and biological literature as d-2-(6'-methoxy-2'-naphthyl)propionic acid.