PHARMACOKINETICS OF ETHYLENE-GLYCOL .3. PLASMA DISPOSITION AND METABOLIC-FATE AFTER SINGLE INCREASING INTRAVENOUS, PERORAL, OR PERCUTANEOUSDOSES IN THE MALE SPRAGUE-DAWLEY RAT

1. The pharmacokinetic fate of [1,2-C-14]-ethylene glycol (EG) was eva luated in the male Sprague-Dawley rat in order to characterize its ove rall uptake and elimination. Doses of 10 and 1000 mg/kg were administe red 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 th e p.o. route. 2. Baseline data obtained by the i.v. route for bioavail ability comparisons showed that while plasma radioactivity concentrati ons declined in a biexponential manner with t(1/2)(beta) of 26-37 h, t he disappearance of unmetabolized EG from the plasma was quite rapid ( t(1/2)(beta) of 0.8-1.2 h). Peroral doses were rapidly and almost comp letely absorbed, showing t(1/2)(beta) in the order of minutes, and a b ioavailable fraction for unmetabolized EG of 92-100%. Conversely, EG a pplied 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 m etabolism to (CO2)-C-14 and exhalation, while urinary elimination of C -14 was the secondary excretion pathway. 4. Plasma clearance of C-14 w as linear with increases in p.o. doses over the 400-800 mg/kg range, w ith AUC proportional to dose for these and the 10 mg/kg p.o. dose leve ls. However, a dose-dependent shift in excretion routes was observed f ollowing the p.o. 1000 mg/kg dose, with urine becoming the major excre tion route, and similar capacity limited pharmacokinetics were observe d for the i.v. 1000 mg/kg dose. Plasma pharmacokinetic data for unchan ged 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 di sappearance of EG. 5. Following both i.v. and p.o. doses, dose-indepen dent relationships were seen in the values obtained for the area under the plasma curve (AUG,), the total clearance of EG (Cl-total(EG)), me an residence time (MRT(infinity)), apparent volume of distribution at steady slate (Vd(SS)), the terminal half-life (t(1/2)(beta)) and the r enal and metabolic clearance values. However, this dose-linear plasma time course was not apparent from the dose-dependent excretion profile s for these two exposure routes. 6. Increases in urinary C-14-glycolat e were also observed when the i.v. or p.o. doses were increased from 1 0 to 1000 mg EG/kg, indicating that metabolism of EG makes a substanti al contribution to AUC(infinity) in the beta disposition phase of the plasma curves for this high dose. Oxalate, a metabolite found in man a fter EG exposure, was detected at very low levels after both the 10 an d 1000 mg/kg dose levels and by either the i.v. or p.o. routes. 7. Thu s, EG given by three different routes demonstrated apparent first-orde r pharmacokinetic behaviour for disposition in and the elimination fro m plasma in the male rat, but dose-dependent changes occurred for the elimination of metabolites in urine and as (CO2)-C-14 after single i.v . and p.o. doses, but not for the p.c. routes.