Comparative Toxicology of Naproxen

Abstract

Naproxen, 4-2-(6′-methoxy-2′-naphthyl)-propionic acid is a compound with demonstrated antiinflammatory activity. In preclinical toxicology studies, the acute oral toxicity was determined in mice, rats, hamsters and dogs. The values for these species in multiples of maximum human therapeutic dose were 107, 47, 357, and >87 respectively. Subacute oral dosing studies were done using mice, rats, rabbits, dogs, monkeys and pigs. These studies showed that repeated oral doses of naproxen were well tolerated by mice, rabbits, monkeys and pigs; less well so by rats and poorly by dogs. Based on these results and pharmacokinetic data, rats, monkeys and pigs were animals of choice for chronic studies. Rats given 2.6 times the human dose per day for 22 months had increased urinary volume, decreased body weight gain and a shorter survival time than control rats or rats given 0.2 or 0.9 times human dose per day. No meaningful changes were seen for monkeys given oral doses of 2.6, 7.8 or 10.4 times human per day for 6 months or for pigs given doses of 0.4, 1.3 or 3.9 times human per day for 1 year. An inhibitory effect on parturition was seen when naproxen was given to rats during the perinatal period. This effect was also seen with other non-steroidal anti-inflammatory agents. Naproxen was not teratogenic when tested in rats or rabbits, nor did it have any effect on fertility. Results from these studies have been compared with those reported for other non-steroidal anti-inflammatory agents.