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Tiopronin protects against the nephrotoxicity of cisplatin in the rat

Department of Pharmacology and Therapeutics, University of Liverpool, P.O. Box 147, Liverpool L69 3BX, UK; Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, WA 99164-6510, USA

M Viale

M Esposito

Istituto Nazionale per la Ricerca sul Cancro, Servizio di Farmacologia Tossicologica, Lgo R. Benzi 10, 16132 Genova, Italy

W E Lindup

Department of Pharmacology and Therapeutics, University of Liverpool, P.O. Box 147, Liverpool L69 3BX, UK

1. 1 Tiopronim (N-(2-mercaptopropionyl)-glycine) is a drug with a free thiol (sulphydryl) group that is used clinically. We have reported previously that tiopronin protects rat kidney slices in vitro from the nephrotoxic effects of cisplatin and does not reduce the antitumour activity of cisplatin. Tiopronin has been investigated therefore for its protective effects in rats in vivo.
   
2. 2 The extent of kidney damage was studied 5 days after the administration of cisplatin. A single injection (i.p.) of cisplatin (6 mg/kg; 20,umollkg) to female Wistar albino rats caused a sustained decrease in body weight and, after 5 days, plasma urea, creatinine and kidney weight were increased. Tiopronin (2.5 mmol/kg, p.o.) ameliorated cisplatin nephrotoxicity when given 1 h before cisplatin. Tiopronin provided marked protection against cisplatin-induced increases in urea (from 237+19 mg to 48+23 mg/100 ml; control: 17+1) and creatinine (from 6.5+0.5 to 1.7+0.5 mg/100 ml control: 1.0 + 0.1). Tiopronin did not, prevent the body weight loss caused by cisplatin. In addition, an intraperitoneal dose (1 mmol/lkg) oftiopronin afforded similar protection to that of an oral dose. Rats that received an i.p. mixture of cisplatin (6 mg/kg) and tiopronin (65 mg/kg) displayed generally less toxicity, as indicated by a small fall in body weight and smaller increases in urea and creatinine and kidney weight.
   
3. 3 The results show that tiopronin protects against cisplatin-induced nephrotoxicity. Oral administration of tiopronin may be a clinically useful way to prevent cisplatin nephrotoxicity.
   

Key Words: tiopronin • cisplatin • nephrotoxicity • antidote • rat

Human & Experimental Toxicology, Vol. 18, No. 12, 713-717 (1999)
DOI: 10.1191/096032799678839644


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