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Effect of route of administration and dose on diabetes-induced protection against cisplatin nephrotoxicity
1Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati Medical Center, Ohio 45267-0004, USA.
Abstract:
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.
Insights
Diabetic rats show reduced kidney damage from cisplatin, a chemotherapy drug. This protection, seen with both i.p. and i.v. cisplatin, suggests diabetes alters kidney cells, offering a form of tolerance to drug toxicity.
Area of Science:
- Nephrology
- Pharmacology
- Endocrinology
Background:
- Diabetic nephropathy is a major complication of diabetes mellitus.
- Kidney resistance to nephrotoxic chemicals is observed in diabetic states.
- Cisplatin is a widely used chemotherapeutic agent with known nephrotoxicity.
Purpose of the Study:
- To investigate the impact of streptozotocin (STZ)-induced diabetes on cisplatin bioavailability, renal accumulation, and nephrotoxicity.
- To determine if diabetes confers protection against cisplatin-induced kidney damage.
- To explore the dose-dependency and route-dependency of this protective effect.
Main Methods:
- Utilized streptozotocin (STZ)-diabetic and non-diabetic rats.
- Administered cisplatin via intraperitoneal (i.p.) and intravenous (i.v.) routes at various doses (2.5-10 mg/kg).
- Measured plasma cisplatin concentrations, renal platinum levels, and blood urea nitrogen (BUN) as indicators of toxicity.
Main Results:
- STZ diabetes impaired cisplatin bioavailability after i.p. but not i.v. administration.
- Renal platinum accumulation and BUN levels were significantly lower in diabetic rats regardless of administration route.
- Diabetes-induced protection was partially reversed by higher cisplatin doses via the i.v. route, with increased renal platinum accumulation.
Conclusions:
- STZ diabetes confers significant protection against cisplatin-induced nephrotoxicity.
- This protection involves both altered bioavailability (i.p. route) and intrinsic renal mechanisms.
- Diabetes appears to induce a state of tolerance rather than absolute resistance in renal tubular cells to cisplatin's effects.