Development of a physiologically based pharmacokinetic model to describe the disposition of methanol in pregnant rats and mice.

Physiologically based pharmacokinetic (PBPK) models have been developed in recent years to describe the disposition of xenobiotics during gestation. These models can account for the dynamics of physiologic changes associated with pregnancy and represent a significant advantage in quantitatively assessing potential exposure of the conceptus. The PBPK approach was used to develop a model of methanol disposition during gestation in rats and mice. To validate this model, concentrations of methanol in the dam and the conceptus were determined after methanol exposure of rats on Gestational Day (gd) 14 and 20 and of mice on gd 18. At the developmental stages examined, the model provided a good description of methanol disposition in the maternal circulation and the conceptus of both species. Furthermore, the model was capable of providing good fits to methanol concentration-time data from the literature. In pregnant animals, conceptal/maternal AUC and Cmax ratios decreased with increasing dose at both gd 14 and gd 20 in the rat and at gd 18 in the mouse. Additionally, the conceptal/maternal diffusion constant ratio consistently decreased with increasing dose in pregnant rats and mice. These results are consistent with earlier observations that methanol limits its own delivery to the conceptus. Further experimentation is required to continue the process of developing a generalized PBPK model to describe the disposition of xenobiotics in pregnancy, to examine specific mechanisms of nonlinear conceptal methanol disposition, and to expand the model to extrapolate to low-dose human exposures.