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

Abstract

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. Temporal data for fraction of dose in plasma [13C10]retinol were modeled using WinSAAM software and a 6-component model with vitamin A intake included as weighted data.

Results: Model-predicted TBS was 198, 533, and 1062 μmol for the Bangladeshi (age, 9-17 mo), Filipino (12-18 mo), and Guatemalan children (35-65 mo). Retinol kinetics were similar for Filipino and Guatemalan groups and generally faster for Bangladeshi children, although fractional transfer of plasma retinol to a larger exchangeable storage pool was the same for the 3 groups. Recycling to plasma from that pool was ∼2.5 times faster in the Bangladeshi children compared with the other groups and the recycling number was 2-3 times greater. Differences in kinetics between groups are likely related to differences in vitamin A stores and intakes (geometric means: 352, 727, and 764 μg retinol activity equivalents/d for the Bangladeshi, Filipino, and Guatemalan children, respectively).

Conclusions: By collecting 1 or 2 blood samples from each child to generate a composite plasma tracer data set with a minimum of 5 children/time, group TBS and retinol kinetics can be estimated in children by compartmental analysis; inclusion of vitamin A intake data increases confidence in model predictions. The super-child modeling approach is an effective technique for comparing vitamin A status among children from different populations. These trials were registered at www.clinicaltrials.gov as NCT03000543 (Bangladesh), NCT03345147 (Guatemala), and NCT03030339 (Philippines).

Keywords: WinSAAM; children; model-based compartmental analysis; retinol; stable isotopes; super-child design; tracer kinetics; vitamin A assessment; vitamin A stores.

Copyright © American Society for Nutrition 2019.

Figures

FIGURE 1

Proposed compartmental model for vitamin A kinetics in children. Circles represent compartments; the rectangles are delay elements; interconnectivities between components (arrows) are fractional transfer coefficients [L(I, J)s, or the fraction of retinol in compartment J transferred to compartment I each day]; and DT(I)s are delay times (or the time spent in delay element I). Delay element 3 is the site of introduction of ingested tracer (*) and dietary vitamin A [U(3)]. Components 3 and 4 represent vitamin A digestion and absorption plus chylomicron processing until vitamin A uptake by hepatocytes (compartment 4). Retinol bound to retinol-binding protein is secreted from compartment 4 into plasma compartment 5, the site of sampling (triangle). Retinol in plasma can exchange with vitamin A in 2 extravascular pools (a larger compartment 6 and a smaller compartment 7) and it can also irreversibly enter component 8, hypothesized to be tissues from which vitamin A does not recycle. Compartment 6 and component 8 are the sites of irreversible loss from the system.

FIGURE 2

Geometric mean observed and model-predicted fraction of dose for [13C10]retinol in plasma simulated to 40 d (A) or 5 d (B) for Bangladeshi, Guatemalan, and Filipino children. Symbols are observed data and lines are model simulations. For the Bangladeshi group, the super-child data set included 5–6 children/time except at 4 d when there were 40 children; for the Filipino group, there were 9–13 children/time and 112 at 4 d; the Guatemalan group included 8–16 children/time and 135 at 4 d. Mean data for each group were fit independently using the model shown in Figure 1. The model-calculated weighted sums of squares for plasma were 6.2E-07, 1.9E-08, and 5.6E-08 for the Bangladeshi, Filipino, and Guatemalan groups, respectively.

FIGURE 3

Geometric mean observed and model-predicted fraction of dose for [13C10]retinol in plasma versus time for Bangladeshi, Guatemalan, and Filipino children. Symbols are observed data and lines are model simulations using the partially parallel model (see Results). For the Bangladeshi group, the super-child data set included 5–6 children/time except at 4 d when there were 40 children; for the Filipino group, there were 9–13 children/time and 112 at 4 d; the Guatemalan group included 8–16 children/time and 135 at 4 d. Mean data for the 3 groups were fit with use of a partially parallel modeling approach (see Methods for details); the model is shown in Figure 1. The model-calculated weighted sums of squares for plasma were 2.4E-07, 4.8E-08, and 8.8E-08 for the Bangladeshi, Filipino, and Guatemalan groups, respectively.