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 and mouse has been developed. The model is superimposed on the normal growth curve for nonpregnant females. It describes the entire gestation period including the period of organogenesis. The model consists of uterus, mammary tissue, maternal fat, kidney, liver, other well-perfused maternal tissues, and other poorly perfused maternal tissues, embryo/fetal tissues, and yolk sac and chorioallantoic placentas. It takes into account the growth of maternal tissues such as uterus, mammary glands, fat, and liver during pregnancy, as well as 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 scaling procedures. Its descriptive utility has been examined with the test chemical 5,5′-dimethyloxazolidine-2,4-dione (DMO), a weak acid that is not bound measurably in plasma or tissues and is eliminated by excretion in the urine. Concentrations of DMO were monitored in maternal rat and embryo plasma and in homogenates of maternal rat muscle and whole embryo after ip administration at 9:00 am 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 at 9:00 am on Day 10 or 11 of gestation required only adjustment for pH's of mouse body fluids.