PHARMACOKINETICS OF ETHYLENE-GLYCOL .1. PLASMA DISPOSITION AFTER SINGLE INTRAVENOUS, PERORAL, OR PERCUTANEOUS DOSES IN FEMALE SPRAGUE-DAWLEY RATS AND CD-1 MICE

The pharmacokinetics of [1,2-C-14]ethylene glycol (EG) were evaluated in female Sprague-Dawley rats and CD-1 mice to characterize the plasma disposition after intravenous (IV), peroral (PO), and percutaneous (P C) doses. Rats were given doses of 10 or 1000 mg/kg by each route, and additional PO doses of 400, 600, or 800 mg/kg. Mice were also given I V and PO (bolus gavage) doses of 10 or 1000 mg/kg, and additional PO d oses of 100, 200, or 400 mg/kg. PC doses in mice were 100 or 1000 mg/k g, and both species were given a 1000 mg/kg PC dose with a 50% (w/w) a queous solution (2 ml/kg) to simulate antifreeze exposure. Results fro m this study have shown that orally-administered EG is very rapidly an d almost completely absorbed in both rats and mice, with a bioavailabl e fraction of 92-100% in rats and similar percentages at the higher do ses in mice. In contrast, the absorption of cutaneously applied EG is comparatively slow in both species. A species difference in the overal l absorption of PC doses was demonstrated, with higher recoveries of C -14 observed after PC doses in mice than for rats and a greater penetr ation of C-14 after applying a 50% aqueous PC dose in mice than in rat s, as evidenced by quantifiable plasma C-14 concentrations only in mic e. The major metabolites in both rats and mice are CO2 and glycolate. Oxidative metabolic pathways are saturated at high PO doses in both sp ecies, resulting in a shift from exhaled CO2 as the major excretion ro ute to urinary excretion. The capacity to metabolize more completely E G to CO2 at low doses seems to be greater in the mouse than in the rat , as evidenced by the absence of urinary oxalate from EG-dosed female mice, and saturation of metabolic pathways at a comparatively lower do se in mice than for rats. This evidence suggests that dose-dependent c hanges in EG excretion in female Sprague-Dawley rats and CD-1 mice pro bably resulted from capacity-limited effects on EG metabolic pathways for the production of CO2 and a compensatory urine clearance of glycol ate. Results from the present study corroborate previous observations in rats for the lower doses, but demonstrate a substantial difference in single-dose pharmacokinetics for IV and PO 1000 mg/kg doses in mice vs. rats. In summary, these data indicate that mice show a nonlinear plasma disposition of total radioactivity (EG and its metabolites) as dose is increased, whereas in rats plasma kinetics were linear over th e dose range evaluated, whereas excretion kinetic patterns were nonlin ear in both species as dose is increased.