Naproxen (+6-methoxy-[alpha-methyl]-2-naphthalene acetic acid) is a nonsteroidal anti-inflammatory drug that is used for the treatment of inflammatory conditions in horses. We developed a model that describes the drug's disposition and renal excretion, including synovial fluid disposition and elimination after IV administration in horses. The plasma disposition, after IV administration of 5 mg/kg of body weight, was described by a two-compartment model; mean +/- SD distribution and elimination half-lives were 1.42 +/- 0.42 and 8.26 +/- 2.56 hours, respectively. Plasma concentration of naproxen after IV administration of 5 mg/kg was 55.3 +/- 13.5 and 0.61 +/- 0.42 mg/L at 5 minutes and 48 hours after its administration, respectively. Steady-state volume of distribution was 0.163 +/- 0.053 L/kg, and area under the plasma concentration time-curve was 372.1 +/- 128.2 mg/h/L. The peak synovial fluid concentration of 12.68 +/- 12.39 mg/L was measured at 6 hours, and decreased to 0.71 +/- 0.38 mg/L at 36 hours after naproxen administration. The decrease of naproxen concentration in synovial fluid paralleled that in plasma. The appearance half-life of naproxen in synovial fluid was 4.64 hours, and the elimination half-life was 6.73 hours. Total body clearance was 0.015 +/- 0.006 L/h/kg. The percentage of plasma protein binding was 97.0 +/- 2.9% at plasma concentrations between 5 and 100 mg/L. This was significantly (P < 0.05) higher than the percentage of binding at plasma concentrations of 0.5, 1, and 500 mg/L, which was 75.2 +/- 11.8%. Most of the drug was excreted as glucuronidated naproxen and unconjugated desmethylnaproxen.(ABSTRACT TRUNCATED AT 250 WORDS)