MODEL DEVELOPMENT AND ANALYSIS OF TENIDAP-INDUCED PROTEINURIA IN THE RAT

Tenidap is a novel antirheumatic agent that causes a mild, reversible proteinuria in human clinical trials. In order to achieve a mechanisti c understanding and safety perspective of the proteinuric effects of t enidap observed in clinical trials, female Sprague-Dawley rats were tr eated with up to 100 mg/kg/day of tenidap in the diet for 4 to 6 weeks followed by a 1- to 6-week reversal period. Pharmacokinetics and meas urements of renal function and histology were assessed during the stud y. Sustained high plasma concentrations of tenidap [area under the pla sma concentration curve (0-24 hr) of 941-1021 mu g . hr/ml and peak pl asma concentration of 61-67 mu g/ml] increased urinary protein, albumi n and phosphate excretion (2- to 8-fold) in rats. These renal effects were reversible within 9 days after removal of the drug. These effects preceded later occurring changes in renal morphology (papillary degen eration and necrosis). There was no evidence of glomerular damage, pro ximal tubule degeneration or necrosis or tubulointerstitial nephritis at the light microscopic level. Other indices of overall renal functio n (glomerular filtration rate, electrolyte and glucose excretion) were unaffected. Examination in situ of microperfused proximal tubules fro m treated rats revealed a 68% decrease in the rate of proximal tubule albumin absorption compared to controls (19 +/- 4 vs. 59 +/- 7 pg/min/ mm, respectively). Fluid absorption rate and bicarbonate handling by t he proximal tubule, along with blood bicarbonate concentrations, pH, P CO2 and PO2, were unaffected by treatment. It was concluded that tenid ap caused a rapid, stable and reversible phosphaturia, microalbuminuri a and proteinuria in the rat. The proteinuric effects were due to impa ired proximal tubule albumin reabsorption that were not associated wit h other signs of impaired renal function or histological evidence of t ubulointerstitial nephritis or proximal tubule/glomerular damage.