A physiologically based pharmacokinetic model for Vitamin A and its Metabolites
Een fysiologisch gebaseerd farmacokinetisch model voor vitamine A en zijn metabolieten
van Veen MP, van Eijkeren JCH, Bode W, Bruil MA, Olling M
RIVM Report 642810003
Vitamin A is an essential food component, which also exhibits teratogenic effects at high dose levels, even following a single peak dose. To study the kinetics of vitamin A and its metabolites in the body, a Physiologically Based Pharmacokinetic model (PB-PK model) for the pregnant rat has been developed. The model describes the concentration of vitamin A and its metabolites in various parts of the pregnant rat body and the developing embryos as a function of time. The model only distinguishes vitamin A and the main groups of metabolites, being the retinyl esters and the retinoic acids. This division recognizes the most important chemical differences that exist. The pregnant rat body was simplified to four body compartments and blood as the transport medium connecting the compartments. The model was fitted to experimental data for vitamin A and retinyl esters derived from experiments at the RIVM, using a continuous background intake and a single peak intake of 300 mg per kg body weight. After the fit, the model was able to describe the time course of vitamin A and its metabolites. Subsequently, the model was applied to the 100 and 1000 mg/kg levels, and the predicted time course stayed within the experimental measured ranges. A sensitivity analysis of the model was performed for those parameters that could not be given values reported in literature or obtained from experiment. The model appeared to be relativily sensitive to changes in the liver vitamin A uptake and release parameters Sr, Smax and Ks, the clearance parameters Clr, Clre and Clra, and the intake rate constant Kin. The model was relativily insensitive to the parameters concerning gut wall metabolism, REmax, Ramax, Kre and Kra.