Copovidone-related Cutaneous Response in the Dog.

A cutaneous response (localized swelling and/or erythema of the skin) has been noted in dog toxicology studies in which multiple, unrelated compounds were administered orally with copovidone as a vehicle. The response has been noted in studies with 6 different test items that are structurally unrelated and span several different therapeutic indications spanning an approximate 6-year period (2009-2015). A factor common among the studies is the formulation-a copovidone amorphous solid dispersion (ASD). Cutaneous responses have not been observed in dogs administered non-ASD formulations of the same test items but have occasionally been noted in placebo (copovidone control) dogs. Polyvinylpyrrolidone (a polymer of one of the primary components of copovidone) has been reported to result in similar findings in dogs when administered by the intravenous route. Considerations for the role of copovidone and the potential role of histamine in the cutaneous changes are outlined.

Aluminum citrate prevents renal injury from calcium oxalate crystal deposition.

Calcium oxalate monohydrate crystals are responsible for the kidney injury associated with exposure to ethylene glycol or severe hyperoxaluria. Current treatment strategies target the formation of calcium oxalate but not its interaction with kidney tissue. Because aluminum citrate blocks calcium oxalate binding and toxicity in human kidney cells, it may provide a different therapeutic approach to calcium oxalate-induced injury. Here, we tested the effects of aluminum citrate and sodium citrate in a Wistar rat model of acute high-dose ethylene glycol exposure. Aluminum citrate, but not sodium citrate, attenuated increases in urea nitrogen, creatinine, and the ratio of kidney to body weight in ethylene glycol-treated rats. Compared with ethylene glycol alone, the addition of aluminum citrate significantly increased the urinary excretion of both crystalline calcium and crystalline oxalate and decreased the deposition of crystals in renal tissue. In vitro, aluminum citrate interacted directly with oxalate crystals to inhibit their uptake by proximal tubule cells. These results suggest that treating with aluminum citrate attenuates renal injury in rats with severe ethylene glycol toxicity, apparently by inhibiting calcium oxalate's interaction with, and retention by, the kidney epithelium.

Role of tissue metabolite accumulation in the renal toxicity of diethylene glycol.

Misuse of diethylene glycol (DEG) has led to numerous epidemic poisonings worldwide. DEG produces toxicity because of its metabolism, although the mechanism of its toxicity has not been further defined. The purpose of this study was to investigate the accumulation of specific metabolites in blood and target organ tissues and to determine the relationship between tissue accumulation of metabolites and the resulting toxicity. Wistar rats were treated with water, 2 g/kg DEG (low dose), 10 g/kg DEG (high dose), or 10 g/kg DEG + fomepizole (15 mg/kg then 10 mg/kg per 12 h, to inhibit DEG metabolism), and blood and tissue samples were collected up to 48 h. After high doses of DEG, 2-hydroxyethoxyacetic acid (HEAA) was the primary metabolite in the blood (∼4 mmol/l), with only low concentrations of diglycolic acid (DGA) (∼0.04 mmol/l). In contrast, renal and hepatic concentrations of DGA and of HEAA at 48 h were similar (∼4 mmol/l), indicating a 100-fold concentrative uptake of DGA by kidney tissue. Treatment with fomepizole blocked the formation of HEAA and DGA and the kidney toxicity. Both HEAA and DGA concentrations in the kidney correlated strongly with the degree of kidney damage. Accumulation of HEAA in blood correlated with increased anion gap and decreased blood bicarbonate so appeared responsible for the DEG-induced acidosis. Although these studies suggest that either metabolite may be involved in producing kidney toxicity, the unexpected renal accumulation of DGA at toxic doses of DEG suggests that it must also be considered a possible toxic metabolite of DEG.

Inhibition of metabolism of diethylene glycol prevents target organ toxicity in rats.

Diethylene glycol (DEG) is an industrial chemical, the misuse of which has led to numerous epidemic poisonings worldwide. The mechanism of its toxicity has not been defined as to the precise relationship between the metabolism of DEG and target organ toxicity. The purpose of this study was to investigate the mechanism for the acute toxicity of DEG, and the effect of the alcohol dehydrogenase inhibitor 4-methylpyrazole (fomepizole), by determining the relationship between accumulation of DEG or its metabolites and the resulting kidney and liver toxicity. Rats were treated by oral gavage with water, 2 g/kg DEG (low dose), 10 g/kg DEG (high dose), or 10 g/kg DEG + fomepizole, and blood and urine were collected over 48 h. Rats treated with high-dose DEG had metabolic acidosis, increased BUN and creatinine, and marked kidney necrosis, noted by histopathology. A minor degree of liver damage was noted at the high dose. After low and high doses of DEG, 2-hydroxyethoxyacetic acid (HEAA) was the primary metabolite in the urine, with only minor amounts of urinary diglycolic acid (DGA). Small amounts of ethylene glycol (EG), but not oxalate or glycolate, were observed in the urine. Treatment with fomepizole blocked the formation of HEAA and DGA and the development of metabolic acidosis and the kidney and liver toxicity. These results indicate that the mechanism for the target organ toxicity results from metabolites of DEG, and not DEG itself nor formation of EG from DEG, and that fomepizole may be a useful antidote for treating DEG poisoning.