Ethylene glycol and glycolate kinetics in rats and dogs.

Ethylene glycol (EG) toxicity results from its metabolism to glycolic acid and other toxic metabolites. The accumulation of glycolate and the elimination kinetics of EG and its metabolites are not well understood, so studies with male Sprague-Dawley rats and mixed breed dogs have been carried out. EG was administered by gavage to rats and dogs, which were placed in metabolic cages for urine and blood sample collection at timed intervals. The peak plasma level of EG occurred at 2 hr after dosing and that of glycolate between 4-6 hr. The rate of EG elimination was somewhat faster in rats with a half-life of 1.7 hr compared to 3.4 hr in dogs. The maximum plasma level of glycolate was greater in rats, although the pattern of accumulation was similar to that in dogs. Glycolate disappeared from the plasma at the same time as EG, suggesting a slower rate of elimination of the metabolite than that of EG. Renal excretion of EG was an important route for its elimination, accounting for 20-30% of the dose. Renal excretion of glycolate represented about 5% of the dose. EG induced an immediate, but short-lived diuresis compared to that in control rats. Minimal clinical effects (mild acidosis with no sedation) were noted at these doses of EG (1-2 g/kg) in both rats and dogs. The results indicate that the toxicokinetics of EG and glycolate were similar in both species.

Ethylene glycol intoxication: evaluation of kinetics and crystalluria.

Ethylene glycol and glycolate kinetics were studied in two cases of ethylene glycol intoxication with maximal ethylene glycol/glycolate concentrations of 40.9/26.8 and 56.4/22.4 mmol/liter, respectively. Both patients survived, but with prolonged renal failure, upon treatment with bicarbonate, ethanol, and hemodialysis. Glycolic acid was the major cause of the metabolic acidosis in both cases; lactate levels were only slightly elevated. Kinetic calculations showed that both ethylene glycol and glycolate were distributed in total body water with plasma half-lives of 8.4 and 7.0 hours, respectively. The half-life of ethylene glycol was increased more than 10-fold by ethanol treatment alone. Calcium oxalate monohydrate crystalluria was dominant in both cases, but in one was preceded by a short period with mainly dihydrate excretion; crystalluria was not present upon admission. Repetitive urine microscopy in search of needle- or envelope-shaped crystals should be performed when ethylene glycol intoxication is suspected.

Ethylene glycol poisoning. The value of glycolic acid determinations for diagnosis and treatment.

Glycolic acid is the ethylene glycol (EG) metabolite that accumulates in the highest concentrations in the blood and may be the major contributing factor to the acute toxicity of EG. Serum and urine levels of glycolic acid have been found to correlate directly with clinical symptoms and mortality in poisoning cases, making it a valuable diagnostic tool. A high pressure liquid chromatographic (HPLC) method for quantitation of glycolic acid in serum was used in several cases of EG ingestion presented to the Louisiana Regional Poison Control Center. The data collected in this study support the value of glycolic acid determination for diagnosis and evaluation of patients poisoned by EG.

High pressure liquid chromatographic assay of 4-methylpyrazole. Measurements of plasma and urine levels.

4-Methylpyrazole (4-MP), a potent competitive inhibitor of alcohol dehydrogenase activity, has potential usefulness as a treatment means for methanol and ethylene glycol poisoning as well as severe disulfiram-ethanol interactions. Further study of the safety and metabolism of 4-MP in human subjects is needed before it can be used in such therapies. An HPLC assay has been developed to measure 4-MP levels in plasma and urine samples. The method was sensitive enough to quantitate 4-MP in an amount as low as 0.1 nmol. Recovery of 4-MP from spiked urine and plasma samples was greater than 90%. 4-MP levels in the plasma and urine of rats injected with an oral dose of 50 mg/kg of body weight were determined; the detectability limit in these samples was about 3 microM. The method is easy to perform and thus has practical application for research laboratories dealing with ethanol metabolism and clinical laboratories desiring to monitor 4-MP levels.

Diagnosis of ethylene glycol (antifreeze) intoxication in dogs by determination of glycolic acid in serum and urine with high pressure liquid chromatography and gas chromatography-mass spectrometry.

A relatively fast and sensitive high pressure liquid chromatographic (HPLC) and gas chromatographic-mass spectrometric (GC/MS) method was developed for determination of glycolic acid, one of the major metabolites of ethylene glycol, in extracts of canine urine and serum. The procedure involves extraction of glycolic acid with methyl ethyl ketone and derivatization with O-p-nitrobenzyl-N,N'-diisopropylisourea (PNBDI) in ethyl acetate solution. Recovery was greater than 94% from spiked samples. Ethylene glycol and commercial antifreeze were administered to experimental dogs at different dosage levels to reproduce the naturally occurring toxicosis associated with the consumption of commercial antifreeze. Glycolic acid was determined in either the urine or serum or both from these dogs by HPLC and GC/MS. 1,3-Butanediol, a competitive inhibitor of ethylene glycol biotransformation, was administered to one dog concurrently with antifreeze. In that experiment, it was effective in decreasing glycolic acid formation and prevented acute metabolic acidosis, kidney damage, and death.