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Pharmacokinetics of 2-Methoxyethanol and 2-Methoxyacetic Acid in the Pregnant Mouse: A Physiologically Based Mathematical Model

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Abstract

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 Gestation Day (GD) 11. Absorption, distribution, and oxidation of 2-ME to 2-MAA and ethylene glycol (EG) were simulated. Flow-limited disposition of 2-ME in maternal tissues was described using in vitro-determined tissue partition coefficients (PCs). The maximum velocity (Vmax) of 2-ME oxidation to 2-MAA was calculated from literature-based in vitro data. Vmax for EG formation, and Michaelis constants for 2-MAA and EG pathways, were estimated from optimized simulations of plasma 2-ME and metabolite 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 from 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 simulate 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 administrations required optimization of first-order 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.

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