DEVELOPMENT OF A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL DESCRIBING 2-METHOXYACETIC ACID DISPOSITION IN THE PREGNANT MOUSE

Using the potent developmental toxicant 2-methoxyethanol (2-ME) as a p rototypical compound, a physiologically based pharmacokinetic (PBPK) m odel was developed to describe the disposition of its primary metaboli te and proximate toxicant 2-methoxyacetic acid (2-MAA) in the pregnant CD-1 mouse. Data were collected during early, mid, and late organogen esis, specifically Gestation Days (GD) 8, 11, and 13 (GD 0 = plug-posi tive date). Pharmacokinetics and tissue partition coefficients for 2-M AA were determined in maternal plasma and conceptus on GD 8 and in mat ernal plasma, embryo, and extraembryonic/amniotic fluid (EAF) on GD 11 and 13. For simulation of GD 8 data, the conceptus was described as a single compartment, combining the yolk sac placenta, embryo, EAF, and decidua. For GD 11 and 13, the placenta, embryo, and EAF were explici tly described. Several hypotheses were tested for their ability to pre dict 2-MAA dosimetry. These hypotheses were encoded as alternative mod els having (a) blood flow-limited delivery of 2-MAA to model compartme nts, (b) pH trapping of ionized 2-MAA within compartments, (c) active transport of 2-MAA into compartments, and (d) reversible binding of 2- MAA within compartments. While the flow-limited description adequately predicted GD 8 dosimetry, the best simulations of the pharmacokinetic data collected on GD 11 and 13 were obtained with the active transpor t models. Since the mechanism by which 2-MAA accumulates into the embr yo and EAF has not yet been elucidated, these mathematical description s are empirical. Further development of this PBPK model for 2-MAA in p regnant mice, in particular its scale-up to humans, will facilitate mo re realistic human risk assessments for the developmental toxicity of 2-ME and related compounds. (C) 1995 Academic Press, Inc.