Use of Population-Based Compartmental Modeling and Retinol Isotope Dilution to Study Vitamin A Kinetics and Total Body Stores among Ghanaian Women of Reproductive Age.

Background: Limited data are available on vitamin A kinetics and total body stores (TBS) in women. Such information can be obtained using compartmental modeling and retinol isotope dilution (RID).

Objectives: Objectives were to apply population-based ("super-subject") modeling to determine retinol kinetics in nonpregnant Ghanaian women of reproductive age and to use RID to predict TBS in the group and its individuals.

Use of the Paired Retinol Isotope Dilution Test, but with a Single Isotope Dose, to Assess the Impact of a Vitamin A Intervention on Vitamin A Stores in Theoretical Children with Low Stores.

Background: As currently applied, the paired retinol isotope dilution (RID) test, which is used to assess the impact of a vitamin A intervention on vitamin A total body stores (TBS), requires 2 doses of stable isotope-labeled vitamin A.

Objectives: The objectives of this study were to evaluate use of a single isotope dose (4 μmol) to assess TBS by RID before and after intervention in theoretical children with low/moderate TBS.

Methods: We selected 6 theoretical children with assigned values for TBS ranging from 82 to 281 μmol.

Use of Theoretical Women and Model-Based Compartmental Analysis to Evaluate the Impact of Vitamin A Intake with or without a Daily Vitamin A Supplement on Vitamin A Total Body Stores and Balance During Lactation.

Background: Inadequate vitamin A (VA) intake is common among lactating women in many communities worldwide, but high-dose VA supplementation for postpartum women is not recommended by the World Health Organization as an effective intervention.

Objectives: To simulate the impact of VA intake via diet and daily VA supplements on VA total body stores (TBS) and balance in theoretical lactating women with low/moderate TBS.

Methods: We studied 6 theoretical subjects with assigned values for TBS from 219-624 μmol.

Use of Compartmental Modeling and Retinol Isotope Dilution to Determine Vitamin A Stores in Young People with Sickle Cell Disease Before and After Vitamin A Supplementation.

Background: Suboptimal plasma retinol concentrations have been documented in US children with sickle cell disease (SCD) hemoglobin SS type (SCD-HbSS), but little is known about vitamin A kinetics and stores in SCD.

Objectives: The objectives were to quantify vitamin A total body stores (TBS) and whole-body retinol kinetics in young people with SCD-HbSS and use retinol isotope dilution (RID) to predict TBS in SCD-HbSS and healthy peers as well as after vitamin A supplementation in SCD-HbSS subjects.

Methods: Composite plasma [C]retinol response data collected from 22 subjects with SCD-HbSS for 28 d after isotope ingestion were analyzed using population-based compartmental modeling ("super-subject" approach); TBS and retinol kinetics were quantified for the group.

Use of Theoretical Subjects to Develop a Method for Assessing Equivalence of Dietary Vitamin A in a Mixed Diet.

Background: Although the vitamin A (VA) equivalency of provitamin A carotenoids from single foods or capsules has been studied using several approaches, there is currently no reliable method to determine VA equivalency for mixed diets.

Objectives: To reach the objective of identifying a method to determine the VA equivalency of provitamin A carotenoids in mixed diets, we tested a new approach using preformed VA as proxy for provitamin A.

Methods: We studied 6 theoretical subjects who were assigned physiologically plausible values for dietary VA intake, retinol kinetic parameters, plasma retinol pool size, and VA total body stores.

Direct Use of Plasma or Milk Vitamin A Specific Activity Data to Model Retinol Kinetics and Predict Vitamin A Stores in Theoretical Lactating Women.

Background: Many applications of the Simulation, Analysis and Modeling software use data on the fraction of an orally administered tracer dose (FD) in plasma; thus, researchers must scale-up measured analyte concentration to the total plasma pool. For studies in lactating women, estimating breast milk pool size is challenging.

Objectives: The objectives were to determine whether the standard vitamin A modeling approach using FD data could be modified to use vitamin A specific activity in milk (SAm) and/or plasma (SAp) for compartmental analysis of vitamin A kinetics and status in theoretical lactating women.

Use of Compartmental Modeling and Datasets for Theoretical Lactating Women to Determine Conditions under Which Vitamin A-Specific Activity in Breast Milk Provides Accurate Estimates of Vitamin A Total Body Stores by Retinol Isotope Dilution.

Background: Vitamin A concentrations in breast milk are related to maternal vitamin A intake and status.

Objectives: Our objective was to identify conditions under which vitamin A specific activity in breast milk (SAm) could be used instead of retinol specific activity in plasma (SAp) to predict vitamin A total body stores (TBS) by retinol isotope dilution (RID).

Methods: We used 12 previously-studied theoretical lactating women with assigned values for TBS (219-1348 μmol) and retinol kinetic parameters; we assumed subjects ingested a dose of stable isotope-labeled vitamin A.

The Use of Datasets for Theoretical Subjects to Validate Vitamin A-Related Methods and Experimental Designs.

We review recent work in which model-based compartmental analysis has been applied to data for theoretical human subjects in order to study questions related to vitamin A kinetics and metabolism. Using model simulations in this way, one can validate experimental designs, evaluate or improve vitamin A assessment methods, study the influence of perturbations on assessment methods, and/or advance information related to retinol kinetics. We also provide some information on the rationale for assigning physiologically appropriate values for specified characteristics [e.

Influence of Vitamin A Status on the Choice of Sampling Time for Application of the Retinol Isotope Dilution Method in Theoretical Children.

Background: Vitamin A status may influence the choice of a blood sampling time for applying the retinol isotope dilution (RID) equation to predict vitamin A total body stores (TBS) in children.

Objectives: We aimed to identify time(s) after administration of labeled vitamin A that provide accurate estimates of TBS in theoretical children with low or high TBS.

Methods: We postulated 2- to 5-y-old children (12/group) with low (<200 μmol) or high TBS (≥700 μmol) and used compartmental analysis to simulate individual subject values for the RID equation TBS =   FaS/SAp (Fa, fraction of dose in stores; S, retinol specific activity in plasma/in stores; SAp, retinol specific activity in plasma).

Does the Amount of Stable Isotope Dose Influence Retinol Kinetic Responses and Predictions of Vitamin A Total Body Stores by the Retinol Isotope Dilution Method in Theoretical Children and Adults?

Background: To minimize both cost and perturbations to the vitamin A system, investigators limit the amount of stable isotope administered when estimating vitamin A total body stores (TBS) by retinol isotope dilution (RID).

Objectives: We hypothesized that reasonable increases in the mass of stable isotope administered to theoretical subjects would have only transient impacts on vitamin A kinetics and minimal effects on RID-predicted TBS.

Methods: We adapted previously used theoretical subjects (3 children, 3 adults) with low, moderate, or high assigned TBS and applied compartmental analysis to solve a steady state model for tracer and tracee using assigned values for retinol kinetic parameters and plasma retinol.

Use of Model-Based Compartmental Analysis and Theoretical Data to Further Explore Choice of Sampling Time for Assessing Vitamin A Status in Groups and Individual Human Subjects by the Retinol Isotope Dilution Method.

Background: An optimal blood sampling time for application of the retinol isotope dilution (RID) method for predicting vitamin A total body stores (TBS) (i.e., vitamin A status) has not been established.

Development of a Compartmental Model to Investigate the Influence of Inflammation on Predictions of Vitamin A Total Body Stores by Retinol Isotope Dilution in Theoretical Humans.

Background: Inflammation, both acute and chronic, is associated with reductions in the synthesis of retinol-binding protein (RBP) and the concentration of retinol in plasma. Consequently, it is currently recommended that the retinol isotope dilution (RID) method not be used to estimate vitamin A total body stores (TBS) in subjects with inflammation.

Objectives: To apply compartmental analysis to study the effects of inflammation on hepatic apo-RBP input, plasma retinol pool size, and RID-predicted TBS in theoretical subjects with known steady state values for these parameters.

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

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.

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

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.

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

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.

Better Predictions of Vitamin A Total Body Stores by the Retinol Isotope Dilution Method Are Possible with Deeper Understanding of the Mathematics and by Applying Compartmental Modeling.

Retinol isotope dilution (RID) is a well-accepted technique for assessing vitamin A status [i.e., total body stores (TBS)].

Use of Model-Based Compartmental Analysis and a Super-Child Design to Study Whole-Body Retinol Kinetics and Vitamin A Total Body Stores in Children from 3 Lower-Income Countries.

Background: Model-based compartmental analysis has been used to describe and quantify whole-body vitamin A metabolism and estimate total body stores (TBS) in animals and humans.

Objectives: We applied compartmental modeling and a super-child design to estimate retinol kinetic parameters and TBS for young children in Bangladesh, Guatemala, and the Philippines.

Methods: Children ingested [13C10]retinyl acetate and 1 or 2 blood samples were collected from each child from 6 h to 28 d after dosing.

Addition of Vitamin A Intake Data during Compartmental Modeling of Retinol Kinetics in Theoretical Humans Leads to Accurate Prediction of Vitamin A Total Body Stores and Kinetic Parameters in Studies of Reasonable Duration.

Background: Mathematical modeling of theoretical data has been used to validate experimental protocols and methods in several fields.

Objectives: We hypothesized that adding dietary vitamin A intake data as an input during compartmental modeling of retinol kinetics would lead to accurate prediction of vitamin A total body stores (TBS) at 2 specified study lengths and would reduce study duration required to accurately define the system.

Methods: We generated reference values for state variables (including TBS and intake) and kinetic parameters for 12 theoretical individuals (4 each of children, younger adults, and older adults) based on modeling plasma retinol tracer data for 365 d.

Inclusion of Vitamin A Intake Data Provides Improved Compartmental Model-Derived Estimates of Vitamin A Total Body Stores and Disposal Rate in Older Adults.

Background: Sampling times and study duration impact estimates of kinetic parameters and variables including total body stores (TBS) and disposal rate (DR) when compartmental analysis is used to analyze vitamin A kinetic data.

Objective: We hypothesized that inclusion of dietary intake (DI) of vitamin A as an additional input would improve confidence in predictions of TBS and DR when modeling results appear to indicate that studies are not long enough to accurately define the terminal slope of the plasma retinol isotope response curve.

Methods: We reanalyzed previously published data on vitamin A kinetics monitored over 52 d in 7 US and 6 Chinese adults (means: 56 y, BMI 26.

A Population-Based (Super-Child) Approach for Predicting Vitamin A Total Body Stores and Retinol Kinetics in Children Is Validated by the Application of Model-Based Compartmental Analysis to Theoretical Data.

Background: Public health nutritionists need accurate and feasible methods to assess vitamin A status and to evaluate efficacy of interventions, especially in children. The application of population-based designs to tracer kinetic data is an effective approach that reduces sample burden for each child.

Objectives: Objectives of the study were to use theoretical data to validate a population-based (super-child) approach for estimating group mean vitamin A total body stores (TBS) and retinol kinetics in children and to use population-based data to improve individual TBS predictions using retinol isotope dilution (RID).

Intestinal β-carotene bioconversion in humans is determined by a new single-sample, plasma isotope ratio method and compared with traditional and modified area-under-the-curve methods.

The vitamin A value (bioefficacy) of provitamin A carotenoids is determined by absorption of the carotenoid (bioavailability) and its subsequent conversion to retinol (bioconversion). Here we show that intestinal bioconversion of β-carotene can be estimated based on analysis of a single plasma sample collected 6 h after subjects ingest a test dose of stable isotope-labeled β-carotene from the ratio of retinyl esters to retinyl esters plus β-carotene. Plasma isotope ratio predictions of bioconversion ranged from 50 to- 93% (mean 76%) for 45 healthy young adults with low vitamin A stores.

A Simple Plasma Retinol Isotope Ratio Method for Estimating β-Carotene Relative Bioefficacy in Humans: Validation with the Use of Model-Based Compartmental Analysis.

Provitamin A carotenoids are an important source of dietary vitamin A for many populations. Thus, accurate and simple methods for estimating carotenoid bioefficacy are needed to evaluate the vitamin A value of test solutions and plant sources. β-Carotene bioefficacy is often estimated from the ratio of the areas under plasma isotope response curves after subjects ingest labeled β-carotene and a labeled retinyl acetate reference dose [isotope reference method (IRM)], but to our knowledge, the method has not yet been evaluated for accuracy.

Should We Restrict Vitamin A Intake, a Minor Contributor to Plasma Retinol Turnover, When Using Retinol Isotope Dilution Equations to Estimate an Individual's Vitamin A Status, or Should Vitamin A Balance Be Maintained?

We discuss whether dietary vitamin A intake should be restricted or maintained at balance when retinol isotope dilution equations are applied to estimate an individual's vitamin A total body stores (TBS) after oral administration of a labeled dose of vitamin A. Although, at first glance, restriction makes sense as a way to prevent dilution of tracer in plasma, further investigation of the assumptions underlying the widely used isotope dilution equation presented by Olson's laboratory in 1989, as well as the compartmental modeling results presented in this article, indicate that, in fact, restriction leads to an incorrect prediction of TBS if steady state retinol isotope dilution equations are applied at the traditional time (21 d). Our results show that newly ingested vitamin A is a minor contributor to total plasma retinol turnover and that restriction of vitamin A intake leads to a higher plasma retinol specific activity than the value obtained when vitamin A input equals output (balance).

Retinol Isotope Dilution Is Applied during Restriction of Vitamin A Intake to Predict Individual Subject Total Body Vitamin A Stores at Isotopic Equilibrium.

Background: Retinol isotope dilution (RID) equations are used to determine vitamin A status and the efficacy of vitamin A intervention programs. Recent work related to RID methods has focused on modifying the "Olson equation" to improve the accuracy of predictions of vitamin A total body stores (TBS) in individual subjects.

Objective: We investigated the hypothesis that short-term restriction of vitamin A intake would result in accurate RID prediction of vitamin A TBS in individuals.

Plasma Retinol Kinetics and β-Carotene Bioefficacy Are Quantified by Model-Based Compartmental Analysis in Healthy Young Adults with Low Vitamin A Stores.

Background: Model-based compartmental analysis of data on plasma retinol kinetics after administration of labeled retinol provides unique information about whole-body vitamin A metabolism. If labeled β-carotene is coadministered, its bioefficacy relative to the retinol reference dose can also be estimated.

Objectives: The objectives were to model plasma retinol kinetics after administration of labeled preformed vitamin A and provitamin A β-carotene and to determine relative β-carotene bioefficacy.