Effect of route of administration and dose on diabetes-induced protection against cisplatin nephrotoxicity.
The kidneys of diabetic rats exhibit resistance to the actions of a variety of nephrotoxic chemicals. Using the streptozotocin (STZ) diabetic rat as a model, the experiments in this study examined the effect of the diabetic state on bioavailability, renal accumulation and renal toxicity following intraperitoneal (i.p.) and intravenous (i.v.) injection of cisplatin at various doses. Comparison of the areas under the plasma concentration versus time curves up to 220 min after cisplatin injection (5 mg/kg body wt) demonstrated that bioavailability of cisplatin was significantly impaired in STZ diabetic versus nondiabetic rats after the i.p. route of administration, but not after the i.v. route. Regardless of the route of cisplatin injection, both renal cortex platinum level and renal toxicity as quantified by blood urea nitrogen (BUN) increase, were significantly lower in STZ diabetic versus nondiabetic rats. Thus, while decreased bioavailability probably plays a role in the protection seen after i.p. injection, renal mechanisms must also be involved since protection was also noted after i.v. injection despite equal bioavailability. To determine whether the protection can be overcome by increasing the dose of cisplatin, renal platinum and BUN levels in STZ diabetics and nondiabetics were compared after i.p. and i.v. cisplatin injections at 2.5, 5, 7.5, and 10 mg/kg body wt. The results demonstrate that the diabetes-induced renal protection can be partially reversed by increased cisplatin dose, but only by the i.v. route. Reversal was accompanied by increased renal platinum accumulation. These results suggest that STZ diabetes alters the tubular cells in a manner that confers protection that more closely resembles tolerance than absolute inherent resistance to the nephrotoxic actions of cisplatin.
Sarangarajan
R
R
Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati Medical Center, Ohio 45267-0004, USA.
Cacini
W
W
D000818:Animals; D001682:Biological Availability; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007333:Insulin Resistance; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D002945:Cisplatin