Development of a compartmental model describing the dynamics of vitamin A metabolism in men.
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 mumol 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, approximately 80% of the absorbed dose was in a compartment that presumably represents stored liver retinyl esters. The model also predicts that approximately 50 mumol of retinol passed through the plasma each day, compared to an estimated utilization rate of 4 mumol/day. This project provides unique and important information about whole-body vitamin A dynamic in humans, and presents approaches to specific modeling issues that may be encountered by others.
Hoffmann-La Roche, Basel, Switzerland.
D
D
von Reinersdorff
M H
MH
Green
J B
JB
Green
D000328:Adult; D000818:Animals; D002247:Carbon Isotopes / Q000032:analysis; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D004224:Diterpenes; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D051381:Rats; D012016:Reference Values; D012176:Retinoids / Q000097:blood; D000084562:Retinyl Esters; D014801:Vitamin A / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*
D002247:Carbon Isotopes; D004224:Diterpenes; D012176:Retinoids; D000084562:Retinyl Esters; D014801:Vitamin A; C014794:retinol palmitate