Physiologically based pharmacokinetic prediction of p-phenylbenzoic acid disposition in the pregnant rat.

Abstract

Disposition of p-phenylbenzoic acid (PPBA) in the pregnant Wistar rat (for both mother and fetuses) was predicted by using a physiologically based pharmacokinetic model. This model was constructed from ten organs for the mother and eight organs for fetuses, with fetal blood flow based on anatomical circulation in uteri and skin-amniotic fluid drug exchange. Plasma total clearance, and renal and nonrenal clearances were measured, and transplacental clearance, skin-amniotic fluid clearances and fetal metabolic clearance were taken from previously reported compartment analysis. Tissue-to-plasma partition coefficients (Kp) for the mother were almost the same as that of the interstitial fluid space (0.055-0.28), except for the kidney and liver. In contrast, Kp values for fetuses were small when membrane restricted and diffusion-limited uptakes were assumed in brain, gut, spleen, muscle, fat, and skin for the mother. The physiological model successfully predicted the PPBA concentration-time profiles for both mother and fetuses after intravenous injection into the mother. Further, the model could be applied to predict the results obtained via two other routes of administration. Fetal plasma PPBA concentrations were well predicted after PPBA injection into umbilical vein and fetal muscle.