Pharmacokinetics of ethylene glycol. III. Plasma disposition and metabolic fate after single increasing intravenous, peroral, or percutaneous doses in the male Sprague-Dawley rat

Abstract

1. The pharmacokinetic fate of [1,2-¹⁴C]-ethylene glycol (EG) was evaluated in the male Sprague-Dawley rat in order to characterize its overall uptake and elimination. Doses of 10 and 1000 mg/kg were administered by the intravenous (i.v.), peroral (p.o.), or percutaneous (p.c.) route; additional doses of 400, 600 and 800 mg/kg were evaluated by the p.o. route.

2. Baseline data obtained by the i.v. route for bioavailability comparisons showed that while plasma radioactivity concentrations declined in a biexponential manner with t_1/2^β of 26–37 h, the disappearance of unmetabolized EG from the plasma was quite rapid (t_1/2^β of 0·8-1·2 h). Peroral doses were rapidly and almost completely absorbed, showing t_1/2^abs in the order of minutes, and a bioavailable fraction for unmetabolized EG of 92–100%. Conversely, EG applied to rat skin was slowly and rather poorly absorbed, showing t_1/2^abs which were an order of magnitude longer than for comparable p.o. and i.v. doses, and a bioavailability of approximately 22%.

3. The major route of elimination for the 10 mg/kg dose by any route was by metabolism to ¹⁴CO₂ and exhalation, while urinary elimination of ¹⁴C was the secondary excretion pathway.

4. Plasma clearance of ¹⁴C was linear with increases in p.o. doses over the 400–800 mg/kg range, with AUC proportional to dose for these and the 10 mg/kg p.o. dose levels. However, a dose-dependent shift in excretion routes was observed following the p.o. 1000 mg/kg dose, with urine becoming the major excretion route, and similar capacity limited pharmacokinetics were observed for the i.v. 1000 mg/kg dose. Plasma pharmacokinetic data for unchanged EG after i.v. and p.o. doses demonstrated an apparent first-order kinetic behaviour between the 10 and 1000 mg/kg dose levels for the disappearance of EG.

5. Following both i.v. and p.o. doses, dose-independent relationships were seen in the values obtained for the area under the plasma curve (AUC_∞), the total clearance of EG (Cl_total^EG), mean residence time (MRT_∞), apparent volume of distribution at steady state (Vd_SS), the terminal half-life (t_1/2^β) and the renal and metabolic clearance values. However, this dose-linear plasma time course was not apparent from the dose-dependent excretion profiles for these two exposure routes.

6. Increases in urinary ¹⁴C-glycolate were also observed when the i.v. or p.o. doses were increased from 10 to 1000 mg EG/kg, indicating that metabolism of EG makes a substantial contribution to AUC_∞ in the β disposition phase of the plasma curves for this high dose. Oxalate, a metabolite round in man after EG exposure, was detected at very low levels after both the 10 and 1000 mg/kg dose levels and by either the i.v. or p.o. routes.

7. Thus, EG given by three different routes demonstrated apparent first-order pharmacokinetic behaviour for disposition in and the elimination from plasma in the male rat, but dose-dependent changes occurred for the elimination of metabolites in urine and as ¹⁴CO₂ after single i.v. and p.o. doses, but not for the p.c. routes.