The nephrotoxicity, cytotoxicity and renal handling of a cisplatin-methionine complex in male Wistar rats.
When cisplatin is administered in the form of a cisplatin-methionine substitution complex, high doses of cisplatin can be tolerated with no obvious signs of renal toxicity. We have demonstrated that male Wistar rats receiving a single i.p. dose of cisplatin-methionine at a 1:5 ratio (by weight) did not exhibit cisplatin-induced nephrotoxicity, while cisplatin administered alone at an identical concentration (6 mg/kg) resulted in marked renal toxicity in all animals treated. Using renal cortical slices prepared from untreated rats, we demonstrated that cisplatin, but not cisplatin-methionine, inhibited the accumulation of 14C-tetraethylammonium (TEA). This observation suggests that cisplatin, unlike cisplatin-methionine, is a substrate for the organic base transport system. In addition, cisplatin alone was more cytotoxic to C6 glioma cells in vitro than the cisplatin-methionine complex. Exposure of C6 glioma cells to cisplatin-methionine, however, resulted in a 50%-60% reduction in 3H-thymidine incorporation at cisplatin:methionine ratios up to 1:10. These results indicate that cisplatin-methionine is significantly cytotoxic yet lacks cisplatin-associated renal toxicity and may, therefore, have a role in the treatment of human malignancies.
Deegan
P M
PM
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Pratt
I S
IS
Ryan
M P
MP
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D001692:Biological Transport; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D004338:Drug Combinations; D005910:Glioma / Q000188:drug therapy; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced*; D008297:Male; D008715:Methionine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured / Q000187:drug effects; D010130:p-Aminohippuric Acid / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D004338:Drug Combinations; D013757:Tetraethylammonium Compounds; C087163:cisplatin, methionine drug combination; D019789:Tetraethylammonium; D008715:Methionine; D002945:Cisplatin; D010130:p-Aminohippuric Acid