Early onset of cisplatin-induced nephrotoxicity in streptozotocin-diabetic rats treated with insulin.

Mechanism of protection against cisplatin nephrotoxicity in streptozotocin-diabetic rats is unclear but is associated with decreased renal platinum accumulation. This study was designed to determine whether normalization of hyperglycaemia by insulin treatment to six week streptozotocin-diabetic rats reversed protection against cisplatin nephrotoxicity. Male Sprague-Dawley rats divided into 3 groups (n=10/group) (1) non-diabetic (2) untreated streptozotocin-diabetic and (3) insulin-treated streptozotocin-diabetic groups were rendered diabetic using streptozotocin (65 mg/kg body weight, intravenous).

Reduced expression of organic cation transporters rOCT1 and rOCT2 in experimental diabetes.

Recent reports have documented a functional deficit of organic cation transport in diabetic rats by an unknown mechanism. This study was designed to test the hypothesis that experimental diabetes decreases expression of organic cation transporters at the basolateral membrane. Streptozotocin-induced diabetic rats were maintained for varying durations after induction of diabetes.

Cellular and molecular studies on cisplatin-induced apoptotic cell death in rat kidney.

Using morphological and molecular approaches, we characterized cisplatin-induced cell necrosis and apoptosis in rat kidney. Male Sprague-Dawley rats ( n=5 per group) received a single intraperitoneal injection of either cisplatin (5 mg/kg) or saline, and were killed on day 5. Functionally, cisplatin-treated rats developed polyuric acute renal failure.

Functional impairment of renal organic cation transport in experimental diabetes.

This study was designed to determine the effect of diabetes on the function of the renal organic cation transport system that mediates the excretion of a wide variety of toxicants and drugs. The experiments compared the ability of renal cortex slices from streptozotocin-induced diabetic and non-diabetic rats to accumulate the model cation, 14C-tetraethylammonium under controlled conditions. Initial experiments demonstrated a progressive decline in tetraethylammonium accumulation with increasing duration of diabetes.

Expression of salt and urea transporters in rat kidney during cisplatin-induced polyuria.

Background: Cisplatin (CP) induced polyuria in rats is associated with a reduction in medullary hypertonicity, normally generated by the thick ascending limb (TAL) salt transporters, and the collecting duct urea transporters (UT). To investigate the molecular basis of this abnormality, we determined the protein abundance of major salt and UT isoforms in rat kidney during CP-induced polyuria.

Methods: Male Sprague-Dawley rats received either a single injection of CP (5 mg/kg, N = 6) or saline (N = 6) intraperitoneally five days before sacrifice.

Expression of renal aquaporins 1, 2, and 3 in a rat model of cisplatin-induced polyuria.

Background: Cisplatin (CP)-induced polyuria in rats is attributed to decreased medullary hypertonicity and/or an end-organ resistance to vasopressin. However, the roles of renal aquaporins (AQPs) have not yet been explored.

Methods: Male Sprague-Dawley rats (230 to 245 g) received either a single injection of CP (5 mg/kg, N = 4) or saline (N = 4) intraperitoneally five days before sacrifice.

Normalization of hyperglycaemia by oral vanadyl sulfate does not reverse diabetes-induced protection against cisplatin nephrotoxicity in streptozotocin-diabetic rats.

Streptozotocin- and galactose-induced diabetic rats are protected against nephrotoxic effects of cisplatin. While the mechanism remains to be defined, protection is associated with a decrease in the accumulation of platinum in renal cortical tissues of streptozotocin-diabetic versus non-diabetic rats. A physiological abnormality common to streptozotocin and galactosemic models of diabetes is hyperglycaemia, suggesting that elevated sugars are involved in mediating protection of diabetic kidney against cisplatin nephrotoxicity.

Determination of biotransformation products of platinum drugs in rat and human urine.

Cisplatin is an extremely effective cancer chemotherapeutic agent, but its use is often accompanied by toxicity. Second generation drugs such as carboplatin are becoming more widely used because of reduced toxicity. Since biotransformation products have been implicated in the toxic responses, we have begun to investigate the reactions of cisplatin and carboplatin with potential biological ligands.

High performance liquid chromatographic assay of amprolium and ethopabate in chicken feed using solid-phase extraction.

A method for the assay of mixtures of amprolium and ethopabate in chicken feed was developed utilizing reversed-phase high-performance liquid chromatography (HPLC) after sample clean-up of a methanolic extract by solid-phase extraction using CN cartridges. HPLC was done with benzocaine as internal standard on a C-8 column with methanol-water 40:60, containing octanesulfonic acid, triethylamine and acetic acid, as mobile phase. Eluate was monitored at 274 nm.

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.

Toxicity and excretion of cisplatin in the avian kidney.

Cisplatin is a widely applied antineoplastic drug with significant nephrotoxic potential. The purpose of this study was to define the toxic effect and excretion of cisplatin in the chicken, a species widely applied to the study of tubular transport mechanisms but little used for toxicology studies. Toxicity was assessed by the relative effect of cisplatin on renal clearances of the standard reference substrates inulin and p-aminohippurate (PAH) and by morphologic assessment of the kidneys of cisplatin-treated chickens.

Reduced renal accumulation and toxicity of cisplatin in experimental galactosemia.

The kidneys of streptozotocin (STZ)-diabetic rats are resistant to certain toxic effects of the antineoplastic drug cisplatin. The mechanism is unknown. This study used the galactosemic rat model to test the hypothesis that the apparent diabetes-induced protection is due to changes in the kidney secondary to chronically elevated hexose concentrations.

Synthesis and renal excretion of technetium-99m-labeled organic cations.

Organic cations are excreted more efficiently than organic anions in uremia suggesting superiority as renal imaging agents. In this study, three 99mTc-labeled cationic cyclam complexes were synthesized and their renal clearance quantified in rats. The complexes are cleared at a rate of about 2.

Renal metallothionein and platinum levels in diabetic and nondiabetic rats injected with cisplatin.

This study was designed to investigate the relationship between the attenuation of cisplatin-induced nephrotoxicity in experimental diabetes and the increased level of renal metallothionein (MT) reported to occur in this condition. Two groups of male Sprague-Dawley rats were used: 42-day streptozotocin diabetics and age-matched nondiabetics. Half of each group was injected with a nephrotoxic dose of cisplatin (5 mg/kg, ip) and half with vehicle.

Concentrative uptake of digoxin by slices of chicken renal cortex.

The purpose of this investigation was to define, under controlled in vitro conditions, the processes contributing to the uptake and accumulation of [3H]digoxin by incubated slices of chicken renal cortex. Progressive uptake was evident in time-course experiments with the slice-to-medium concentration ratio (S/M) reaching 5.25 after 120 min.

Accumulation of aluminum by rabbit renal cortex.

Aluminum is a ubiquitous metal with significant toxic potential for humans. It is eliminated principally by the kidney, however the mechanisms involved remain obscure. The purpose of this study was to define and quantify the uptake process for aluminum by incubated slices of rabbit kidney cortex.

Animal model for theophylline--cimetidine drug interaction.

Cimetidine (300 mg I.V.) and theophylline (15 mg/kg I.

Uptake of trimethoprim by renal cortex.

The purpose of this study was to examine the mechanisms involved in the uptake of the urinary antibacterial drug trimethoprim by incubated slices of rat renal cortex. Concentration-dependent studies of the uptake process demonstrated that a saturable component was involved. The results of inhibitor studies as well as the time-course pattern support the conclusion that at least two processes are involved in the uptake of trimethoprim.

Accumulation of cimetidine by kidney cortex slices.

The mechanisms involved in the excretion of the histamine H2-receptor antagonist cimetidine are as yet incompletely understood. The purpose of this study was to examine the interaction of cimetidine with incubated slices of dog kidney cortex. The results of time and concentration-dependent experiments by using 3H-labeled cimetidine demonstrated that the drug was accumulated without metabolism against a concentration gradient by a saturable process.

Effect of co-trimoxazole and sulfamethoxazole on serum creatinine in normal subjects.

Significant elevation of serum creatinine concentration and reduction in creatinine clearance have been reported following cotrimoxazole therapy in patients with normal and impaired renal function. Both components of co-trimoxazole, trimethoprim and sulfamethoxazole, have been proposed as the causative agent. Ten healthy male volunteers were treated for seven days with either sulfamethoxazole (5 subjects) or co-trimoxazole (5 subjects) in the usual recommended doses.

Comparative accumulation of uric acid and hypoxanthine by slices of avian renal cortex.

The purpose of the study was to compare the concentrative uptake processes of the 14C-labeled purines uric acid (UA) and hypoxanthine (HX) by slices of chicken renal cortex. It was found that both purines were accumulated by the slices and that, while UA was unaltered metabolically, HX was partially oxidized to UA during the incubation. Inhibition of the oxidation of HX to UA by use of the enzyme inhibitor allopurinol did not alter accumulation indicating that metabolism of HX did not drive accumulation.

Quantification of renal uric acid synthesis in the rat.

The excretion of nephrogenic uric acid in the urine of Sprague-Dawley rats was estimated by use of the isotope-dilution technique. In nonfasted rats the urine-to-plasma specific activity ratio (SAR) of [14C]uric acid was 0.93, suggesting that a minimum of 7% of the uric acid excreted in the urine is synthesized in the kidney.

The excretion of coumarin and hydroxycoumarins by the avian kidney in vivo.

The mechanics involved in the renal excretion of C14-labeled coumarin (C), 7-hydroxycoumarin (7HC) and 4-hydroxycoumarin (4HC) were studied in unanesthetized chickens by use of the Sperber technique. Analysis of urine collected during unilateral portal infusion of C, 4HC or 7HC indicated that the chicken excreted these coumarins almost entirely in conjugated form. Both 7HC and 4HC appeared in the urine only as the corresponding glucuronide.