scholarly journals Parameter identifiability and Extended Multiple Studies Analysis of a compartmental model for human vitamin A kinetics: fixing fractional transfer coefficients for the initial steps in the absorptive process

2013 ◽  
Vol 111 (6) ◽  
pp. 1004-1010 ◽  
Author(s):  
Hyunjin Park ◽  
Michael H. Green
Keyword(s):  
Vitamin A ◽  
Simulation Analysis ◽  
Serum Vitamin ◽  
Absorption Efficiency ◽  
Study Data ◽  
Retinol Binding Protein ◽  
Transfer Coefficients ◽  
Retinyl Acetate ◽  
Parameter Identifiability ◽  
Modeling Software

In the existing compartmental models of human vitamin A metabolism, parameters related to the absorption of the isotopic oral dose have not been well identified. We hypothesised that fixing some poorly identified parameters related to vitamin A absorption would improve parameter identifiability and add statistical certainty to such models. In the present study, data for serum vitamin A kinetics in nine subjects given [2H8]retinyl acetate orally and a model with absorption fixed at 75 % were used to test this hypothesis. In addition to absorption efficiency, we fixed two other fractional transfer coefficients: one representing the initial processing of the ingested dose and the other representing the direct secretion of retinol bound to retinol-binding protein (RBP) from enterocytes into the plasma. The Windows version of Simulation, Analysis and Modeling software (WinSAAM) was used to fit serum tracer data v. time for each subject. Then, a population model was generated by WinSAAM's Extended Multiple Studies Analysis. All the parameters had fractional standard deviations < 0·5, and none of the pairs of parameters had a correlation coefficient >0·8 (accepted criteria for well-identified parameters). Similar to the values predicted by the original model, total traced mass for retinol was 1160 (sd 468) μmol, and the time for retinol to appear in the plasma bound to RBP was 31·3 (sd 4·4) h. In conclusion, we suggest that this approach holds promise for advancing compartmental modelling of vitamin A kinetics in humans when the dose must be administered orally.

scholarly journals Updated Estimates of Vitamin a Total Body Stores in Healthy Young Adults Determined by Compartmental Modeling with Vitamin a Intake Added as Data (FS06-07-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Jennifer Ford ◽  
Georg Lietz ◽  
Anthony Oxley ◽  
Joanne Green ◽  
Michael Green
Keyword(s):  
Young Adults ◽  
Vitamin A ◽  
Model Prediction ◽  
Simulation Analysis ◽  
Geometric Mean ◽  
Compartmental Analysis ◽  
Science Research ◽  
European Ancestry ◽  
Retinyl Acetate ◽  
Total Body

Abstract Objectives We applied a new modeling approach to generate estimates of vitamin A total body stores (TBS) for previously-studied subjects (Green et al. J Nutr 2016;146:2129–36) who were consuming moderate amounts of preformed vitamin A. Based on recent work, we hypothesized that inclusion of an estimate of vitamin A dietary intake (DI) during modeling would help compensate for the less-than-optimal study duration (14 d). Methods We reanalyzed retinol kinetic data collected after ingestion of [13C10]retinyl acetate by 26 young adults of European ancestry for whom estimates of DI were available. To predict TBS by compartmental analysis, geometric mean (GM) data on fraction of dose in plasma versus time plus estimated intake (2.9 µmol retinol activity equivalents/d) were analyzed using the Simulation, Analysis and Modeling software in light of previously-established models. We also used modeling to estimate coefficients (“FaS”) used in retinol isotope dilution (RID) equations and calculated TBS for the group and individuals. Results TBS predicted by the model without DI data included was 98 µmol; when the GM DI was included in the modeling data stream, predicted TBS was 273 µmol. Including DI data during modeling also resulted in lower predictions of intake [2.9 versus 8.7 µmol/d without DI, compared with the average RDA for adults (2.8 µmol/d)] and longer predicted days of vitamin A stores (125 versus 15 d). Using the FaS at 7 d (0.90) predicted by the model with DI, RID-predicted TBS agreed with the model prediction (GM, 274 µmol, range 106–889 µmol). Conclusions Results indicate that including an estimate of DI during modeling provides more realistic predictions of TBS for studies of short duration and improves confidence in model prediction of vitamin A status. Funding Sources Original human studies were supported by Biotechnology and Biological Science Research Council (grant BB/G004056/1 to GL) and Cancer Research UK; current analyses were supported by College of Health and Human Development, Penn State University.

scholarly journals Effects of food or nutrient restriction on milk vitamin A transfer and neonatal vitamin A stores in the rat

1990 ◽  
Vol 63 (2) ◽  
pp. 351-362 ◽  
Author(s):  
Ana Maria ◽  
G. Pasatiempo ◽  
A. Catharine Ross
Keyword(s):  
Vitamin A ◽  
Maternal Diet ◽  
Control Diet ◽  
Serum Vitamin ◽  
Liver Weight ◽  
Retinol Binding Protein ◽  
Serum Retinol ◽  
Total Food Intake ◽  
Affect Transfer ◽  
Liver Vitamin

We have investigated the effects of maternal diets low in fat or protein, or restricted in total food intake on vitamin A transfer from the dam to her pups. When animals were fed on diets moderately restricted in fat or protein, minimal differences in milk, serum, and liver vitamin A concentrations were observed compared with animals fed on a control diet. In a second study, dams were fed on diets more severely restricted in protein, or fat, or both, or were fed on a control diet equal to 50% of the intake of control rats but containing an equal amount of vitamin A. The quantity of milk obtained from these more severely restricted dams' nipples or the pups' stomachs was greatly reduced; however, there were no differences in milk vitamin A concentration. Body-weight, liver weight, and total liver vitamin A stores of undernourished pups were just half those measured for control pups, although serum vitamin A and serum retinol-binding protein were nearly normal in concentration. We conclude that (a) moderate restrictions in fat or protein in the maternal diet are insufficient to affect transfer of vitamin A to the suckling pup; (b) further dietary restrictions could cause decreased milk production with little change in milk vitamin A concentration and, hence, (c) the neonates' hepatic retinol accumulation during the suckling period is markedly reduced when maternal diets are severely deficient in fat or protein or of normal composition but restricted in amount.

scholarly journals Vitamin A Absorption Efficiency Determined by Compartmental Analysis of Postprandial Plasma Retinyl Ester Kinetics in Theoretical Humans

2020 ◽  
Vol 150 (8) ◽  
pp. 2223-2229 ◽  
Author(s):  
Michael H Green ◽  
Joanne Balmer Green ◽  
Jennifer Lynn Ford
Keyword(s):  
Vitamin A ◽  
Simulation Analysis ◽  
Theoretical Data ◽  
Absorption Efficiency ◽  
Compartmental Modeling ◽  
Dietary Recommendations ◽  
Response Curves ◽  
Stable Isotope Label ◽  
Sample Number ◽  
Retinyl Ester

ABSTRACT Background Better methods are needed for determining vitamin A absorption efficiency in humans to support development of dietary recommendations and to improve the accuracy of predictions of vitamin A status. Objectives We developed and evaluated a method for estimating vitamin A absorption efficiency based on compartmental modeling of theoretical data on postprandial plasma retinyl ester (RE) kinetics. Methods We generated data on plasma RE and retinol kinetics (30 min to 8 h or 56 d, respectively) after oral administration of labeled vitamin A for 12 theoretical adults with a range of values assigned for vitamin A absorption (55–90%); we modeled all data to obtain best-fit values for absorption and other parameters using Simulation, Analysis, and Modeling software. We then modeled RE data only (16 or 10 samples), with or without added random error, and compared assigned to predicted absorption values. We also compared assigned values to areas under RE response curves (RE AUCs). Results We confirmed that a unique value for vitamin A absorption cannot be identified by modeling plasma retinol tracer kinetics. However, when RE data were modeled, predicted vitamin A absorptions were within 1% of assigned values using data without error and within 12% when 5% error was included. When the sample number was reduced, predictions were still within 13% for 10 of the 12 subjects and within 23% overall. Assigned values for absorption were not correlated with RE AUC (P = 0.21). Conclusions We describe a feasible and accurate method for determining vitamin A absorption efficiency that is based on compartmental modeling of plasma RE kinetic data collected for 8 h after a test meal. This approach can be used in a clinical setting after fasting subjects consume a fat-containing breakfast meal with a known amount of vitamin A or a stable isotope label.

scholarly journals Vitamin A Absorption Determined in Rats Using a Plasma Isotope Ratio Method

2020 ◽  
Vol 150 (7) ◽  
pp. 1977-1981 ◽  
Author(s):  
Michael H Green ◽  
Joanne Balmer Green
Keyword(s):  
Vitamin A ◽  
Oral Dose ◽  
Isotope Ratio ◽  
Cholesterol Absorption ◽  
Absorption Efficiency ◽  
Intravenous Dose ◽  
Ratio Method ◽  
Sprague Dawley ◽  
Retinyl Acetate ◽  
Dose Fraction

ABSTRACT Background Better methods are needed for determining vitamin A absorption efficiency. Objective Our objective was to measure vitamin A absorption in rats by adapting a plasma isotope ratio method previously used to determine cholesterol absorption. Methods Male Sprague-Dawley rats [n = 14; 340 ± 16 g (mean ± SD)] received an oral tracer dose of [3H]retinyl acetate in oil plus an intravenous dose of [14C]vitamin A–labeled lymph prepared in a donor rat that had received [14C]retinyl acetate intraduodenally. Blood samples were collected on days 1, 2, 3, 6, 9, and 12, and plasma was analyzed for 3H and 14C; vitamin A absorption was calculated for each sample as (fraction of oral dose/fraction of intravenous dose) × 100. Radioactivity was also measured in feces and urine collected as pools on days 3, 6, 9, and 12 and in liver and remaining carcass on day 12. Results Vitamin A absorption calculated as the plasma isotope ratio was &gt;100% on day 1, 78% ± 5% on day 6, 76% ± 5% on day 9, and 74% ± 5% on day 12; fitting the data to an exponential function plus a constant predicted an absorption of 75% by day 14. Recovery of the oral dose in feces (day 0 to day 6) was low (6.2% ± 0.84%, n = 10) and the mean isotope ratio in day 9–12 urine pool was lower than that in plasma. Conclusions The plasma isotope ratio holds promise for estimating vitamin A absorption, but additional work is needed to determine how long studies need to be and if the doses should be administered simultaneously. For application of this method in humans, artificial chylomicrons labeled with a stable isotope of retinyl acetate could be used for the intravenous dose, with a different isotope required for the oral dose.

scholarly journals Validation of a Method for Estimating Vitamin A Absorption Efficiency Based on Compartmental Analysis of Post-Prandial Plasma Retinyl Ester Kinetics

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 108-108
Author(s):  
Michael Green ◽  
Jennifer Ford ◽  
Joanne Green
Keyword(s):  
Vitamin A ◽  
Simulation Analysis ◽  
Compartmental Analysis ◽  
Population Based ◽  
Absorption Efficiency ◽  
Average Error ◽  
Response Curves ◽  
Retinyl Ester ◽  
Free Data ◽  
Gates Foundation

Abstract Objectives Because good methods are not available to estimate vitamin A (VA) absorption, we evaluated an approach based on modeling retinyl ester response to an oral VA dose. Methods We generated data for 12 theoretical subjects, assigning values for VA absorption, stores, and kinetic parameters; we used WinSAAM (Simulation, Analysis and Modeling software) to simulate data (without and with 5% average error) for plasma chylomicron retinyl esters (RE) and retinol versus time (30 min to 8 h or 56 d, respectively) after ingestion of labeled VA; next we fit data to a previously-published 9-component model for VA metabolism to obtain “known” values for VA absorption. Then RE data only were modeled for each subject using a robust (n = 16 times) vs truncated sampling schedule (n = 10) and model-predicted absorptions were compared to known values. Areas under the plasma RE response curves (AUCs) were also calculated and compared to known absorption values. Results Known values for VA absorption based on modeling all data with error ranged from 54 – 92% (mean, 72%), VA stores from 160 – 1775 μmol, and chylomicron t1/2 from 6 – 12 min. Using the full sampling scheme for RE, the ratio of model-predicted to known absorption ranged from 0.927 – 1.06 (mean, 0.997); using the truncated scheme, the ratio was 0.814 – 1.13 (mean, 0.973). AUCs were not significantly correlated with known values for VA absorption (R2 = 0.112; P &gt; 0.05), presumably because absorption and chylomicron catabolism are occurring simultaneously. Conclusions By modeling chylomicron RE tracer data after ingestion of labeled VA, absorption efficiency was estimated accurately using error-free data; using data with 5% error, estimates were within 10% of known values (full sampling) or within 20% (truncated). If subjects, after an overnight fast, consume a breakfast containing some fat and a known amount of VA, then no tracer is required to estimate VA absorption using this modeling approach. By incorporating a population-based design, the method could be used in children. Funding Sources Supported by Bill & Melinda Gates Foundation (Project Number OPP1115464) and HarvestPlus (BH183438).

Serum vitamin A, retinol-binding protein, and prealbumin concentrations in protein-calorie malnutrition

1973 ◽  
Vol 26 (9) ◽  
pp. 982-987 ◽  
Author(s):  
Frank Rees Smith ◽  
DeWitt S. Goodman ◽  
Guillermo Arroyave ◽  
Fernando Viteri
Keyword(s):  
Vitamin A ◽  
Binding Protein ◽  
Serum Vitamin ◽  
Retinol Binding Protein ◽  
Protein Calorie Malnutrition

scholarly journals A Compartmental Model Describing the Kinetics of β-Carotene and β-Carotene-Derived Retinol in Healthy Older Adults

2020 ◽  
Author(s):  
Michael H Green ◽  
Jennifer Lynn Ford ◽  
Joanne Balmer Green
Keyword(s):  
Vitamin A ◽  
Compartmental Model ◽  
Quantitative Information ◽  
Complex Model ◽  
Retinol Binding Protein ◽  
Whole Body ◽  
Published Data ◽  
Retinyl Acetate ◽  
Kinetics Of ◽  
Β Carotene

ABSTRACT Background Descriptive and quantitative information on β-carotene whole-body kinetics in humans is limited. Objectives Our objective was to advance the development of a physiologically based, working hypothesis compartmental model describing the metabolism of β-carotene and β-carotene-derived retinol. Methods We used model-based compartmental analysis (Simulation, Analysis and Modeling software) to analyze previously published data on plasma kinetics of [2H8]β-carotene, [2H4]β-carotene-derived retinol, and [2H8]retinyl acetate-derived retinol in healthy, older US adults (3 female, 2 male; 50–68 y); subjects were studied for 56 d after consuming doses of 11 μmol [2H8]β-carotene and, 3 d later, 9 μmol [2H8]retinyl acetate in oil. Results We developed a complex model for labeled β-carotene and β-carotene-derived retinol, as well as preformed vitamin A, using simulations to augment observed data during model calibration. The model predicts that mean (range) β-carotene absorption (bioavailability) was 9.5% (5.2–14%) and bioefficacy was 7.3% (3.6–14%). Of the absorbed β-carotene, 41% (25–58%) was packaged intact in chylomicrons and the balance was converted to retinol, with 58% (42–75%) transported as retinyl esters in chylomicrons and 0–2% by retinol-binding protein. Most (95%) chylomicron β-carotene was cleared by the liver. Later data revealed differences in the metabolism of retinyl acetate- versus β-carotene-derived retinol; data required that both β-carotene and derived retinol be recycled from extrahepatic tissues (e.g. adipose) in HDL. Of total bioconversion [73% (47–99%)], 82% occurred in the intestine, 17% in the liver, and 0.83% in other tissues. Conclusions Our model advances knowledge about whole-body β-carotene metabolism in healthy adults, including the kinetics of transport in all lipoprotein species, and suggests hypotheses to be tested in future studies, such as the possibility that retinol derived from hepatic conversion over a long period of time might contribute to plasma retinol homeostasis and total body vitamin A stores.

Sign in / Sign up

Export Citation Format

Share Document