Development of a Compartmental Model Describing the Dynamics of Vitamin A Metabolism in Men

Abstract

Model-based compartmental analysis was used with the Simulation, Analysis and Modeling (SAAM) computer programs to analyze data on plasma retinoid kinetics in adult male subjects for 7 d after a single oral dose of 105 μmol of [8,9,19-¹³C]retinyl palmitate. We present here the data for one subject and discuss in detail the steps taken to develop a physiologically-based compartmental model that describes the dynamic behavior of plasma retinyl esters, [¹²C]retinol, [8,9,19-¹³C]retinol, and the sum of [¹²C] and [¹³C]retinol.

First an absorption model was developed to fit data on the plasma appearance and disappearance of retinyl esters; this was used as input in development of models for labeled and unlabeled retinol. The large oral load of labeled vitamin A perturbed the unlabeled tracee system, and thus parallel models for tracer and tracee were developed; and a time-variant fractional transfer coefficient was incorporated into the tracee model. Following the absorption model, four-compartment models were developed to describe the dynamics of both labeled and unlabeled retinol.

These models predict that, in spite of the large vitamin A load, the absorption efficiency was 34%; hepatic (presumably parenchymal cell) processing of the absorbed dose was essentially complete by 24 h; and, by 7 days, ~80% of the absorbed dose was in a compartment that presumably represents stored liver retinyl esters. The model also predicts that ~50 μmol of retinol passed through the plasma each day, compared to an estimated utilization rate of 4 μmol/day. This project provides unique and important information about whole-body vitamin A dynamics in humans, and presents approaches to specific modeling issues that may be encountered by others.