The relative nephrotoxicity of cisplatin, cis-[Pt(NH3)2(guanosine)2]2+, and the hydrolysis product of cisplatin in the rat.
An examination of the comparative nephrotoxicity in the rat of cisplatin, its hydrolysis product (mostly cis-[Pt(NH3)2Cl(H2O)]+ under the conditions applied), and cis-[Pt(NH3)2(guanosine)2]2+ revealed that these compounds differed significantly in the extent of renal damage they produced following their i.v. injection in Sprague-Dawley rats. The hydrolysis product was found to be the most toxic of the three complexes studied and produced nephrotoxicity at doses lower than those at which cisplatin was nephrotoxic. Under the conditions used, the i.v. administration of cis-[Pt(NH3)2(guanosine)2]2+ resulted in no observable signs of nephrotoxicity at levels at which an equimolar dose of cisplatin produces clear evidence of renal function impairment and morphological alterations. The nephrotoxicity of these complexes appears to be generally related to the ease with which they undergo nucleophilic substitution reactions. The lack of substantial nephrotoxicity found for cis-[Pt(NH3)2(guanosine)2]2+ suggests that the products resulting from the action of the DNA repair processes on platinated DNA do not contribute significantly to the nephrotoxicity of cisplatin. Renal platinum levels found following the administration of these compounds correlated with the degree of nephrotoxicity produced by each compound, but no general correlation of nephrotoxicity and renal platinum levels was found. The nephrotoxicity of cis-[Pt(NH3)2Cl(H2O)+ on a molar basis was estimated to be approximately 3 times as great as that of cisplatin itself.
Jones
M M
MM
Department of Chemistry, Vanderbilt University, Nashville, TN 37235.
Basinger
M A
MA
Beaty
J A
JA
Holscher
M A
MA
D000818:Animals; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity*; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006868:Hydrolysis; D007668:Kidney / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D008657:Metabolic Clearance Rate / Q000187:drug effects; D010984:Platinum / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains
C071963:cisplatin-guanosine adduct; D010984:Platinum; D003404:Creatinine; D002945:Cisplatin