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 mechanistic understanding and safety perspective of the proteinuric effects of tenidap observed in clinical trials, female Sprague-Dawley rats were treated 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 measurements of renal function and histology were assessed during the study. Sustained high plasma concentrations of tenidap [area under the plasma concentration curve (0-24 hr) of 941-1021 micrograms. hr/ml and peak plasma concentration of 61-67 micrograms/ml] increased urinary protein, albumin 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 degeneration and necrosis). There was no evidence of glomerular damage, proximal tubule degeneration or necrosis or tubulointerstitial nephritis at the light microscopic level. Other indices of overall renal function (glomerular filtration rate, electrolyte and glucose excretion) were unaffected. Examination in situ of microperfused proximal tubules from 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 the proximal tubule, along with blood bicarbonate concentrations, pH, PCO2 and PO2, were unaffected by treatment. It was concluded that tenidap caused a rapid, stable and reversible phosphaturia, microalbuminuria and proteinuria in the rat. The proteinuric effects were due to impaired proximal tubule albumin reabsorption that were not associated with other signs of impaired renal function or histological evidence of tubulointerstitial nephritis or proximal tubule/glomerular damage.
Aleo
M D
MD
Pfizer Incorporated, Central Research Division, Groton, Connecticut, USA.
Wang
T
T
Giebisch
G
G
Sanders
M J
MJ
Walsh
A H
AH
Lopez-Anaya
A
A
D000418:Albumins / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000493:pharmacokinetics; D001639:Bicarbonates / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004573:Electrolytes / Q000097:blood; D005260:Female; D007211:Indoles / Q000009:adverse effects* / Q000493:pharmacokinetics; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D000078183:Oxindoles; D011507:Proteinuria / Q000139:chemically induced*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016482:Urinalysis
D000418:Albumins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001639:Bicarbonates; D004573:Electrolytes; D007211:Indoles; D000078183:Oxindoles; C062866:tenidap