PHYSIOLOGICAL CONSTANTS FOR PBPK MODELS FOR PREGNANCY

Physiologically based pharmacokinetic (PBPK) models for pregnancy are inherently more complex than conventional PBPK models due to the growt h of the maternal and embryo/fetal tissues. Physiological parameters s uch as compartmental volumes or flow rates are relatively constant at any particular time during gestation when an acute experiment might be conducted, but vary greatly throughout the course of gestation (e.g., contrast relative fetal weight during the first month of gestation wi th the ninth month). Maternal physiological parameters change during g estation, depending upon the particular system; for example, cardiac o utput increases by similar to 50% during human gestation; plasma prote in concentration decreases during pregnancy; overall metabolism remain s fairly constant. Maternal compartmental volumes may change by 10-30% ; embryo/fetal volume increases over a billionfold from conception to birth. Data describing these physiological changes in the human are av ailable from the literature. Human embryo/fetal growth can be well des cribed using the Gompertz equation. By contrast, very little of these same types of data is available for the laboratory animal. In the rode nt there is a dearth of information during organogenesis as to embryo weights, and even less organ or tissue weight or volume data during em bryonic or fetal periods. Allometric modeling offers a reasonable choi ce to extrapolate (approximately) from humans to animals; validation, however, is confined to comparisons with limited data during the late embryonic and fetal periods of development (after gestation d 11 in th e rat and mouse). Embryonic weight measurements are limited by the sma ll size of the embryo and the current state oi technology. However, th e application of the laser scanning confocal microscope (LSCM) to opti cally section intact embryos offers the capability of precise structur al measurements and computer-generated three-dimensional reconstructio n of early embryos. Application of these PBPK models of pregnancy in l aboratory animal models at teratogenically sensitive periods of develo pment provides exposure values at specific target tissues. These expos ures provide fundamentally important data to help design and interpret molecular probe investigations into mechanisms of teratogenesis.