Toxicologic Pathology

 

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Toxicologic Pathology, Vol. 27, No. 3, 295-306 (1999)
DOI: 10.1177/019262339902700305

Renal Changes Associated with Naproxen Sodium Administration in Cynomolgus Monkeys

Michael W. Leach

Schering-Plough Research Institute, Lafayette, New Jersey 07848, michael.leach{at}spcorp.com.

Doyle W. Frank

Schering-Plough Research Institute, Lafayette, New Jersey 07848

Mark R. Berardi

Schering-Plough Research Institute, Lafayette, New Jersey 07848

Ellen W. Evans

Schering-Plough Research Institute, Lafayette, New Jersey 07848

Robert C. Johnson

Schering-Plough Research Institute, Lafayette, New Jersey 07848

David G. Schuessler

Schering-Plough Research Institute, Lafayette, New Jersey 07848

Elaine Radwanski

Schering-Plough Research Institute, Kenilworth, New Jersey 07033

Mark E. Cartwright

Schering-Plough Research Institute, Lafayette, New Jersey 07848

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.

Key Words: Naproxen • nonsteroidal anti-inflammatory drugs • pharmacokinetics • kidney • nephritis • cynomolgus monkey • toxicity


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[Abstract] [Full Text] [PDF]