PHARMACOKINETICS OF 2-METHOXYETHANOL AND 2-METHOXYACETIC ACID IN THE PREGNANT MOUSE - A PHYSIOLOGICALLY-BASED MATHEMATICAL-MODEL

A physiologically based pharmacokinetic (PBPK) model was created to describe the disposition of 2-methoxyethanol (2-ME) and its teratogenic metabolite, 2-methoxyacetic acid (2-MAA), in the pregnant CD-1 mouse. The model’s foundation is a mathematical description of the physiological changes that occur during gestation (O’Flaherty et al., Toxicol. Appl. Pharmacol. 112, 245-256, 1992). The PBPK model was developed and validated with data collected on Gestational Day (GD) 11. Absorption, distribution, and oxidation of 2-ME to 2-MAA and ethylene glycol (EG) were stimulated. Flow-limited disposition of 2-ME in maternal tissues was described using in vitro-determined tissue partition coefficients (PCs). The maximum velocity (V(max)) of 2-ME oxidation to 2-MAA was calculated from literature-based in vitro data. V(max) for EG formation, and Michaelis constants for 2-MAA and EG pathways, were estimated from optimized simulations of plasma 2-ME and metabolic levels obtained after intravenous injection of 5-600 mg 2-ME·kg-1. 2-MAA disposition and elimination in the dam were described by a nonphysiological one-compartment model, which was linked to the 2-ME model, based on the volume of distribution (0.510 liters·kg-1) and overall elimination rate constant (0.124 hr-1) calculated friom iv 2-MAA plasma concentration-time courses. Transfer of 2-MAA between the placenta and conceptus was described as a diffusion-limited process to more accurately simulated the higher concentrations of 2-MAA determined in embryonic compartments compared with maternal plasma levels. Subsequent 2-MAA disposition within the embryo proper and surrounding fluid of the GD 11 conceptus was adequately described using embryo/blood (0.94) and extraembryonic fluid/blood (1.33) PCs. Extension of the PBPK model to oral and subcutaneous 2-ME administration required optimization of first-oder absorption rates; model simulations agreed closely with measured 2-ME/2-MAA levels. With refinements and further validation, the PBPK model of 2-ME/2-MAA disposition should prove helpful for extrapolation throughout gestation and between species. © 1994 Academic Press. All rights reserved.