Comparison of the effects of ethanol and 4-methylpyrazole on the pharmacokinetics and toxicity of ethylene glycol in the dog

Abstract

The purpose of this investigation was to compare the effects of ethanol and 4-methylpyrazole (4MP) on the toxicity and pharmacokinetics of ethylene glycol (EG) in the dog. All dogs received 173 mmol kg EG, p.o. Dogs were randomly assigned to 3 groups: EG-treated only, EG + ethanol (19.3 mmol kg , i.v. 3, 7, 14 and 24 h after EG) and EG + 4MP (0.24 mmol kg , i.v. 3 h after EG, 0.18 mmol kg at 24 h and 0.06 mmol kg at 36 h). EG produced a rapid onset of metabolic acidosis (within 3 h) and acute oliguric renal failure (after 48 h), whereas administration of ethanol or 4MP greatly attenuated acidosis and prevented renal toxicity. The administration of ethanol, however, severely increased the central nervous system (CNS) depression that existed after ingestion of EG. The half-life of EG in serum was 10.8 ± 0.7 h in the EG-only treatment group, 6.8 ± 0.7 ( P<0.05) in the EG + ethanol group and 9.8° 0.9 h in the EG + 4MP group. Approx. 10% and 48% of the dose of EG was excreted unchanged in the urine at the 0–3 and 3–72 h periods, respectively. Treatment with 4MP increased the amount of EG excreted in the urine (71% from 3–72 h), whereas ethanol did not (51%). However, both ethanol and 4MP increased the rate constant of EG excretion into urine approx. 70%. These data demonstrate the utility of 4MP over ethanol for the treatment of EG-induced toxicity in dogs and indicate that ethanol and 4MP cause an increase in the rate constant of EG excretion in the urine and not a prolongation in EG half-life.