Renal Changes Associated with Naproxen Sodium Administration in Cynomolgus Monkeys

Naproxen sodium was administered to cynomolgus monkeys (Macaca fascicularis) by oral gavage at daily doses of 44, 88, or 176 mg/kg for 2 wk (2 monkeys/gender) or of 44 mg/kg for 13 wk (4 monkeys/gender). Body weight loss occurred in at least one monkey in all naproxen sodium-dosed groups in the 2-wk (up to 16% loss) and 13-wk (up to 22% loss) studies. Increases in plasma naproxen concentrations were dose proportional between 44 and 88 mg/kg but were less than dose proportional between 88 and 176 mg/kg. Up to 2-fold increases in creatinine and/or serum urea nitrogen values as well as higher renal weights occurred in monkeys receiving 176 mg/kg for 2 wk or 44 mg/kg for 13 wk. Microscopically, renal changes were observed in all naproxen sodium-dosed groups. Renal findings after 2 wk of exposure included increased interstitial ground substance, tubular dilatation, and tubulointerstitial nephritis; in the 13-wk study, cortical tubular atrophy and interstitial fibrosis were also observed. These studies identify the kidney as the target organ of naproxen sodium in cynomolgus monkeys.