PLASMA AND SYNOVIAL-FLUID KINETICS, DISPOSITION, AND URINARY-EXCRETION OF NAPROXEN IN HORSES

Naproxen (+6-methoxy-[alpha-methyl]-2-naphthalene acetic acid) is a no nsteroidal anti-inflammatory drug that is used for the treatment of in flammatory conditions in horses. We developed a model that describes t he drug's disposition and renal excretion, including synovial fluid di sposition and elimination after IV administration in horses. The plasm a disposition, after IV administration of 5 mg/kg of body weight, was described by a two-compartment model; mean +/- SD distribution and eli mination half-lives were 1.42 +/- 0.42 and 8.26 +/- 2.56 hours, respec tively. 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 hou rs after its administration, respectively. Steady-state volume of dist ribution was 0.163 +/- 0.053 L/kg, and area under the plasma concentra tion time-curve was 372.1 +/- 128.2 mg/h/L. The peak synovial fluid co ncentration of 12.68 +/- 12.39 mg/L was measured at 6 hours, and decre ased to 0.71 +/- 0.38 mg/L at 36 hours after naproxen administration. The decrease of naproxen concentration in synovial fluid paralleled th at in plasma. The appearance half-life of naproxen in synovial fluid w as 4.64 hours, and the elimination half-life was 6.73 hours. Total bod y clearance was 0.015 +/- 0.006 L/h/ kg. The percentage of plasma prot ein 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. The recovery of naproxen and all metabolites in urine at 36 hours was 64.6 +/- 7.2% of the total dose. Of this total, 39.6 +/- 10.3% and 8.5 rt 7.9% were glucuronidated napr oxen and desmethylnaproxen, respectively; 0.3 +/- 0.1% and 16.6 +/- 7. 9% were free naproxen and desmethylnaproxen, respectively.