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 develope d in recent years to describe the disposition of xenobiotics during ge station. These models can account for the dynamics of physiologic chan ges associated with pregnancy and represent a significant advantage in quantitatively assessing potential exposure of the conceptus, The PBP K 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 e xposure 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 desc ription of methanol disposition in the maternal circulation and the co nceptus of both species. Furthermore, the model was capable of providi ng good fits to methanol concentration-time data from the literature, In pregnant animals, conceptal/maternal AUC and C-max 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 met hanol limits its own delivery to the conceptus. Further experimentatio n is required to continue the process of developing a generalized PBPK model to describe the disposition of xenobiotics in pregnancy, to exa mine specific mechanisms of nonlinear conceptal methanol disposition, and to expand the model to extrapolate to low-dose human exposures. (C ) 1997 Academic Press.