PHYSIOLOGICALLY-BASED PHARMACOKINETIC PREDICTION OF P-PHENYLBENZOIC ACID DISPOSITION IN THE PREGNANT RAT

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 orga ns 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 we re measured, and transplacental clearance, skin-amniotic fluid clearan ces and fetal metabolic clearance were taken from previously reported compartment analysis. Tissue-to-plasma partition coefficients (K-p) fo r the mother were almost the same as that of the interstitial fluid sp ace (0.055-0.28), except for the kidney and liver. In contrast, K-p va lues for fetuses were small when membrane restricted and diffusion-lim ited uptakes were assumed in brain, gut, spleen, muscle, fat, and skin for the mother. The physiological model successfully predicted the PP BA concentration-time profiles for both mother and fetuses after intra venous 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 inje ction into umbilical vein and fetal muscle. (C) 1998 John Wiley & Sons , Ltd.