A Physiologically Based Kinetic Model of Rat and Mouse Gestation: Disposition of a Weak Acid

Abstract

A physiologically based toxicokinetic model of gestation in the rat mouse has been developed. The model is superimposed on the normal growth curve for nonpregnant females. It describes the entire gestation period including organogenesis. The model consists of uterus, mammary tissue, maternal fat, kidney, liver, other well-perfused and poorly perfused maternal tissues, embryo/fetal tissues, and yolk sac and chorioallantoic placentas. It takes into account the growth of maternal tissues during pregnancy, and growth of the conceptus. The gestation model is based on published values of organ volumes and blood flows for the rat throughout pregnancy. It is scaled to the mouse using conventional procedures. Its utility has been examined with the test chemical 5,5'-thyloxazolidine-2,4-dione (DMO). Concentrations of DMO were monitored in maternal rat and embryo plasma and in homogenates of maternal rat muscle and whole embryo after ip administration on Day 13 of gestation. On the basis that distribution of DMO is determined solely by its pK and the pH's of body fluids, pH and excretion rate values were estimated by visual optimization of model predictions to the concentration profile. Successful prediction of concentrations of DMO in the same tissues of pregnant mice after its ip administration on Day 10 or 11 of gestation required only adjustment for pH's of mouse body fluids.

Citation

O'Flaherty, E., W. Scott, C. Schreiner, AND R. Beliles. A Physiologically Based Kinetic Model of Rat and Mouse Gestation: Disposition of a Weak Acid. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-92/240 (NTIS PB92198647).

Additional Information

Toxicology and Pharmacology 112:245-256

• A PHYSIOLOGICALLY BASED KINETIC MODEL OF RAT AND MOUSE GESTATION: DISPOSITION OF A WEAK ACID