Dose-dependent nonlinear pharmacokinetics of ethylene glycol metabolites in pregnant (GD 10) and nonpregnant Sprague-Dawley rats following oral administration of ethylene glycol.
The kinetics of orally administered ethylene glycol (EG) and its major metabolites, glycolic acid (GA) and oxalic acid (OX), in pregnant (P; gestation day 10 at dosing, GD 10) rats were compared across doses, and between pregnant and nonpregnant (NP) rats. Groups of 4 jugular vein-cannulated female rats were administered 10 (P and NP), 150 (P), 500 (P), 1000 (P), or 2500 (P and NP) mg (13)C-labelled EG/kg body weight. Serial blood samples and urine were collected over 24-hr postdosing, and analyzed for EG, GA, and OX using GC/MS techniques. Pharmacokinetic parameters including Cmax, Tmax, AUC, and betat((1/2)) were determined for EG and GA. Pregnancy status (GD 10-11) had no impact on the pharmacokinetic parameters investigated. Blood levels of GA were roughly dose-proportional from 10 to 150 mg EG/kg, but increased disproportionately from 500 to 1000 mg EG/kg. EG and GA exhibited dose-dependent urinary elimination at doses > or = 500 mg EG/kg, probably due to saturation of metabolic conversion of EG to GA, and of GA to downstream metabolites. The shift to nonlinear kinetics encompassed the NOEL (500 mg EG/kg) and LOEL (1000 mg EG/kg) for developmental toxicity of EG in rats, providing additional evidence for the role of GA in EG developmental toxicity. The peak maternal blood concentration of GA associated with the LOEL for developmental toxicity in the rat was quite high (363 microg/g or 4.8 mM blood). OX was a very minor metabolite in both blood and urine at all dose levels, suggesting that OX is not important for EG developmental toxicity.
Pottenger
L H
LH
Toxicology and Environmental Research and Consulting, Dow Europe, SA, Horgen, Switzerland. lpottenger@dow.com
Carney
E W
EW
Bartels
M J
MJ
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D002247:Carbon Isotopes; D004305:Dose-Response Relationship, Drug; D019855:Ethylene Glycol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006016:Glycolates / Q000493:pharmacokinetics*; D017711:Nonlinear Dynamics; D019815:Oxalic Acid / Q000493:pharmacokinetics*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D002247:Carbon Isotopes; D006016:Glycolates; C031149:glycolic acid; D019815:Oxalic Acid; D019855:Ethylene Glycol