PHARMACOKINETIC AND LOCAL TISSUE DISPOSITION STUDIES OF NAPROXEN FOLLOWING TOPICAL AND SYSTEMIC ADMINISTRATION IN DOGS AND RATS

The pharmacokinetic profiles of naproxen in blood and synovial fluid ( SF) following topical and i.v. bolus administration in dogs, and the l ocal tissue disposition of the drug following topical and oral adminis tration in rats, were investigated to assess the feasibility of topica l delivery of naproxen for local and systemic effects. The naproxen ge l in poloxamer 407 (PF-127) was applied on the stifle joint of dogs, a nd serum and synovial fluid samples were collected. For local tissue d isposition studies, the naproxen gel was applied on the dorsal skin in rats, and blood, skin, and muscle samples were taken at 3, 6, and 12 h postdose after removing the residual gel from the skin, Steady state serum concentrations occurred at similar to 20 h after topical doses and lasted for the next similar to 30 h in dogs. Similar SF-serum conc entration ratios of naproxen were found between i.v. (0.61+/-0.16) and topical (0.55+/-0.14) routes of administration. Following the i.v. do se, the half-life of naproxen in SF (similar to 60 h) was significantl y longer than that in serum (similar to 40 h). The bioavailability of naproxen in the topical gel was similar to 2% of the applied dose in d ogs. A large accumulation of drug in the epidermis, dermis, and muscle tissue beneath the gel application site was found in rats. Isopropyl myristate (IPM) significantly increased the systemic absorption as wel l as the concentrations of naproxen in the underlying dermis and muscl e tissues, but exerted little effect on the disposition of naproxen in the epidermis. (C) 1997 by John Wiley & Sons, Ltd.