BACKGROUND:Retinol isotope dilution (RID) equations are used to predict vitamin A total body stores (TBS). Including population-based ("super-subject") modeling with RID provides group-specific values for the equation coefficients. OBJECTIVES:The objective was to test an approach that would accommodate a limited super-subject sample size without compromising accuracy in RID predictions of TBS. METHODS:We used Simulation, Analysis and Modeling software to simulate fraction of dose in plasma (FDp) at 16 times from 3 h to 56 d after tracer ingestion in 20 theoretical adults. Then, we modeled geometric mean FDp ("full dataset") to determine group mean TBS and the coefficients Fa (FD in stores) and S (specific activity in plasma/stores) in the RID equation TBS (μmol) = FaS/plasma retinol specific activity. Using the same FDp data, we also generated 4 datasets with reduced subject numbers at times other than that designated for RID (day 21). Then, we adjusted individual FDp using the ratio (individual FDp on day 21/mean FDp on day 21; "adjusted datasets"), modeled each, and determined TBS and FaS for comparison with the full dataset values. RESULTS:Mean ratio of model-predicted TBS for adjusted/full dataset was 0.962 (range: 0.920-1.06) and for FaS, it was 0.945 (day 14), 0.971 (day 21), and 0.984 (day 28). CONCLUSIONS:For these theoretical data, adjusting individual FDp values based on relationship to the group mean FDp at an appropriate time (21 d) maintains the accuracy of model predictions of TBS and the RID composite coefficient FaS. If these results are confirmed using real data, values for FaS determined in a small super-subject study can be applied to confidently predict TBS by RID in that group's individuals. This approach will be especially useful when resources are limited for studies of vitamin A status in community settings.

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. Using Simulation, Analysis, and Modeling software and a previously published compartmental model for whole-body VA metabolism, we simulated TBS over 6 mo of established lactation for each subject under 4 conditions: 1) prelactation VA intake was increased to maintain VA balance (LSS); 2) prelactation VA intake was maintained (NLSS); 3) VA intake was the same as 2) but a daily VA supplement (2.8 μmol/d) was added (NLSS+S); and 4) VA intake was as 1) and the daily VA supplement was included (LSS+S). RESULTS:To compensate for the loss of VA via milk while VA balance was maintained (LSS) over 6 mo of lactation, VA intake had to increase by 0.8-1.87 μmol/d (n = 6) compared with NLSS. Over 6 mo of NLSS treatment, VA balance was negative (geometric mean, -0.77 μmol/d) compared with LSS, whereas balance was positive under NLSS+S and LSS+S conditions (0.75 and 1.5 μmol/d, respectively). For LSS, the proportion of total VA disposal was 37% via breastmilk, 32% from VA stores, and 32% from nonstorage tissues. CONCLUSIONS:Adding a daily VA supplement (2.8 μmol/d) to the diet of lactating women with suboptimal VA intake may effectively counterbalance the negative VA balance resulting from the output of VA via breastmilk and thus benefit both mother and infant by maintaining or increasing VA stores and breastmilk VA concentration.

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. Methods: Women (n 1 / 4 89) ingested a dose of [2H6]retinyl acetate and blood samples (3/woman) were collected from 6 h to 91 d, with all participants sampled at 14 d, about half at either 21 or 28 d, and each at one other time. Composite data (plasma retinol fraction of dose; FDp) were analyzed using Simulation, Analysis and Modeling software to obtain kinetic parameters, TBS, and other state variables as well as model-derived values for the RID composite coefficient FaS. The latter were used in the RID equation TBS (mu mol) 1 / 4 FaS x 1/SAp (where SAp is plasma retinol specific activity) to predict TBS at various times. Results: Model-predicted TBS was 973 mu mol (n 1 / 4 87). Geometric mean RID-predicted TBS was 965, 926, and 1006 mu mol at 14, 21, and 28 d, respectively, with wide ranges [for example, 252-3848 mu mol on day 14 (n 1 / 4 86)]; TBS predictions were similar at later times. Participants had a mean 2 y of vitamin A in stores and estimated liver vitamin A concentrations in the normal range. Model-predicted vitamin A disposal rate was 1.3 mu mol/d and plasma recycling number was 37. Conclusions: Super-subject modeling provides an estimate of group mean TBS as well as group-specific values for the RID coefficient FaS; the latter can be used to confidently predict TBS by RID for individual participants in the group under study or in similar individuals at 14 d or more after isotope ingestion. Trial registration number: Trial is registered (NCT04632771) at https://clinicaltrials.gov.

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 mu mol) 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 mu mol. Using Simulation, Analysis and Modeling software, we simulated the variable [plasma retinol specific fi c activity (SAp)] p )] and coefficients fi cients (Fa Fa and S ) used in the RID equation TBS (mu mol) mu mol) = FaS x 1/SAp p in both the unsupplemented steady state at day 14 postdosing and during the subsequent 4 mo without or with vitamin A supplementation [2.8 mu mol retinol/d (801 mu g retinol activity equivalents/d)]. Results: Fraction of dose in plasma on day 150 compared with day 14 was similar in the unsupplemented and supplemented conditions [geometric mean, 32% (range, 20%-48%) - 48%) and 30% (20%-48%), - 48%), respectively] and simulated values for FaS were similar under the 2 conditions. After 2 and 4 mo of daily vitamin A supplementation with 2.8 mu mol/d, TBS was 78% and 128% higher, respectively, than without supplementation. Conclusions: Results indicate that the paired RID method can successfully be done using a single 4 mu mol dose of stable isotope. Furthermore, because values for the RID coefficient fi cient FaS were similar in the unsupplemented and vitamin A-supplemented conditions, these results in theoretical children indicate that FaS determined by population ("super " super-subject") " ) modeling of steady state vitamin A kinetic data could be used to predict TBS by RID after a vitamin A intervention in individuals from the same or a similar group.

Fatty acids (FA) differ in their transfer efficiencies and metabolic partitioning and lactating cows provide a robust model to investigate kinetics of FA transport. The objective was to compare kinetics of n-3 polyunsaturated FA (PUFA) trafficking through plasma and into milk. In the first experiment, ten ruminally cannulated multiparous Holstein cows were used in a crossover design with 7 d periods. Cows were milked at 6 h intervals and abomasal treatments provided a single dose of 80.1 g of alpha-linolenic acid as free FA (ALA-FFA) or 45.5 g EPA and 32.9 g DHA (LCn3-FFA). Transfer of n-3 PUFA to milk was nearly 50% higher for ALA-FFA than LCn3-FFA (48.2 and 32.7% of the bolus) and fit a bi-exponential model. Rapid transport of n-3 PUFA, assumed to be directly through chylomicrons, was nearly twice as high in ALA-FFA than LCn3-FFA and the subsequent slow transport, assumed to be indirect transfer through tissue recycling, was over 2.5-fold higher in LCn3-FFA than in ALA-FFA. Plasma analysis revealed LCn3-FFA enriched phospholipids and cholesterol esters, which had a slow clearance. In the second experiment, 4 cows received a bolus of a mixture of ALA, EPA, and DHA prepartum while not lactating and around d 10, 55, and 225 of lactation. Transfer of ALA to milk did not differ between stages of lactation, but DHA was lower in early compared to mid and late lactation. In conclusion, dietary ALA is rapidly and efficiently transferred to milk in cows while EPA and DHA are rapidly incorporated into plasma or tissue fractions not available to the mammary gland. This demonstrates clear differences in trafficking and partitioning of n-3 PUFA that ultimately impact tissue and organelle enrichment with implications for effective doses.

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 pa-rameters, plasma retinol pool size, and VA total body stores. Using features in the Simulation, Analysis and Modeling software, we specified that subjects ingested a tracer dose of stable isotope-labeled VA on day 0 followed by 0-& mu;g supplemental VA or 200, 400, 800, 1200, 1600, and 2000 & mu;g VA daily from day 14 to day 28; we assigned VA absorption to be 75%. For each supplement level, we simulated plasma retinol specific activity (SAp) over time and calculated the mean decrease in SAp relative to 0 & mu;g. Group mean data were fitted to a regression equation to calculate predicted VA equivalency at each supplement level on day 28. Results: For each subject, higher VA supplement loads resulted in lower SAp, with the magnitude of the decrease differing among subjects. The mean predicted amount of absorbed VA was within 25% of individual subjects' assigned amount for 4 of the 6 subjects, and the mean ratio of predicted to assigned amount of absorbed VA over all supplement loads ranged from 0.60 to 1.50, with an overall mean ratio of 1.0. Conclusions: Results for preformed VA suggest that this protocol may be useful for determining VA equivalency of provitamin A carot-enoids in free-living subjects if mixed diets with known provitamin A content were substituted for the VA supplements.

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 [13C10]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. TBS was also calculated for the same individuals using RID, as well as for healthy peers (n = 20) and for the subjects with SCD-HbSS after 8 wk of daily vitamin A supplements (3.15 or 6.29 μmol retinol/d [900 or 1800 μg retinol activity equivalents/d]). RESULTS:Model-predicted group mean TBS for subjects with SCD-HbSS was 428 μmol, equivalent to ∼11 mo of stored vitamin A; vitamin A disposal rate was 1.3 μmol/d. Model-predicted TBS was similar to that predicted by RID at 3 d postdosing (mean, 389 μmol; ∼0.3 μmol/g liver); TBS predictions at 3 compared with 28 d were not significantly different. Mean TBS in healthy peers was similar (406 μmol). RID-predicted TBS for subjects with SCD-HbSS was not significantly affected by vitamin A supplementation at either dose. CONCLUSIONS:Despite differences in plasma retinol concentrations, TBS was the same in subjects with SCD-HbSS compared with healthy peers. Because 56 d of vitamin A supplementation at levels 1.2 to 2.6 times the Recommended Dietary Allowance did not increase TBS in these subjects with SCD-HbSS, further work will be needed to understand the effects of SCD on retinol metabolism. This trial was registered as NCT03632876 at clinicaltrials.gov.

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 (SA(m)) could be used instead of retinol specific activity in plasma (SA(p)) 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 mu mol) and retinol kinetic parameters; we assumed subjects ingested a dose of stable isotope-labeled vitamin A. We expanded a 9-compartment steady state tracer model to include a parallel model for tracee (unlabeled retinol) and then adapted that model so vitamin A intake entered the system in 3 meals each day. Using compartmental analysis, we first simulated SA(m) and SA(p) after an overnight fast (as in actual RID experiments) and then with vitamin A intake also restricted in sequential meals on the day before sampling for RID. Results After an overnight fast, SA(m) at day 21 postdosing was lower than SA(p). However, if vitamin A intake was also restricted in 1, 2, or 3 meals before sampling, SA(m)/SA(p) (mean +/- SD) was 0.92 +/- 0.042, 0.96 +/- 0.016, or 0.99 +/- 0.004, respectively; results for days 14 and 28 were similar. When either SA(p) or SA(m) was used to predict TBS by RID on day 21 after 1-d restriction, predictions for all subjects were within 25% of assigned TBS. Conclusions Results indicate that, for theoretical lactating women with a wide range of vitamin A status, SA(m) will accurately predict TBS by RID at 2-4 wk postdosing if vitamin A intake is restricted for 1 d before sampling. If confirmed in community settings, results suggest that vitamin A status in lactating women can be determined without collecting blood.

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.g., plasma retinol concentration, vitamin A total body stores (TBS), vitamin A intake] to hypothetical individuals, and in addition, we outline how one might first select an appropriate compartmental model for whole-body vitamin A metabolism and then specify physiologically reasonable values for the associated retinol kinetic parameters. In the studies discussed here, the Simulation, Analysis, and Modeling software was used to simulate responses in key model compartments for hypothetical subjects so that model predictions could be compared to assigned values or projected outcomes. For example, in the case of the retinol isotope dilution (RID) method that is used to assess vitamin A status, application of this approach has provided a way to evaluate the accuracy of TBS predictions under different steady state and non-steady state conditions, thus increasing confidence about the validity of RID results obtained in the field. Although datasets for theoretical subjects have been used to evaluate protocols in pharmacokinetics, to our knowledge, other nutrition researchers have not previously used approaches such as those described here. Our results to date indicate that this strategy has the potential to provide useful information related not only to vitamin A but perhaps to other nutrients as well.

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. To follow retinol trafficking when increasing amounts of stable isotope were administered [1.39-7 (children) and 2.8-14 mu mol retinol (adults)], we added assumptions to an established compartmental model so that plasma retinol homeostasis was maintained. Using model-simulated data, we plotted retinol kinetics versus time and applied the RID equation TBS = FaS/SA(p) [Fa, fraction of dose in stores; S, retinol specific activity (SA) in plasma/SA in stores; SA(p), SA in plasma] to calculate vitamin A stores. Results: The model predicted that increasing the stable isotope dose caused transient early increases in hepatocyte total retinol; increases in plasma tracer were accompanied by decreases in tracee to maintain plasma retinol homeostasis. Despite changes in kinetic responses, RID accurately predicted assigned TBS (98-105%) at all loads for all theoretical subjects from 1 to 28 d postdosing. Conclusions: Results indicate that, compared with doses of 1.4-3.5 mu mol, used in recent RID field studies, doubling the stable isotope dose should not affect the accuracy of TBS predictions, thus allowing for experiments of longer duration when including a super-subject design (Ford et al., J Nutr 2020;150:411-8) and/or studying retinol kinetics.

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 (SA(m)) and/or plasma (SA(p)) for compartmental analysis of vitamin A kinetics and status in theoretical lactating women. Methods Using 12 previously studied theoretical subjects with a wide range of assigned values for vitamin A total body stores (TBS) and the coefficient ("FaS") needed to predict TBS using a retinol isotope dilution equation, we simulated data for SA(p) and SA(m) for 49 d after oral administration of labeled vitamin A. Then we modeled datasets for SA(p) and SA(m), as well as only SA(p) or SA(m), incorporating a linear scaling factor to automatically convert SA to FD and including several physiologically reasonable constraints as input data. As outcomes, we compared model-predicted TBS and FaS to assigned values. Results Scaling factors effectively adjusted SA data to adequately predict vitamin A mass in plasma and breast milk pools. Data for SA(p) and SA(m) provided model predictions of TBS that were comparable to assigned values (range: 85-107%); using only SA(p), ratios ranged from 92% to 108% and for SA(m) from 85% to 108%. Parallel results were obtained for simulated FaS. Conclusions Results show that SA data from plasma and/or milk can be used directly for modeling vitamin A during lactation in theoretical subjects, providing accurate estimates of TBS and FaS. Results suggest that, in free-living lactating women, researchers might measure only SA(p) or only SA(m) and adequately describe whole-body vitamin A metabolism and status.

BACKGROUND:Low vitamin A status and suboptimal milk vitamin A concentrations are problems in many populations worldwide. However, limited research has been done on whole-body vitamin A kinetics in women of reproductive age, especially during lactation. OBJECTIVES:Goals were to develop compartmental models describing retinol kinetics in theoretical nonlactating (NL) and lactating (L) women and to determine whether the retinol isotope dilution (RID) method accurately predicted vitamin A total body stores (TBS) in the groups and individuals. METHODS:We adapted 12 previously-used theoretical females with assigned values for retinol kinetic parameters and TBS (225-1348 μmol); subjects were NL or L (nursing one 3- to 6-mo-old infant) during 49-d kinetic studies after isotope dosing. We used an established compartmental model, adding a compartment for chylomicrons and, for L, another for mammary gland milk with inputs from holo-retinol-binding protein and chylomicron retinyl esters and output to milk. Using compartmental analysis, we simulated tracer responses in compartments of interest and calculated TBS using the RID equation TBS =   FaS/SAp [Fa, fraction of dose in stores; S, retinol specific activity in plasma/specific activity in stores; SAp, specific activity of retinol in plasma]. RESULTS:Models for both groups were well identified. Simulated plasma tracer responses were similar for NL and L, with L always below NL; milk tracer paralleled plasma from 10 d postdosing. Geometric mean FaS ratios (L/NL) were ∼0.75 during days 2-30. Using appropriate group FaS, RID provided accurate TBS predictions for >80% of NL and L subjects after day 18 when CV% for FaS was ∼10%. CONCLUSIONS:These new physiologically-based models for vitamin A kinetics may be useful for future research in women of reproductive age. Results indicate that, in groups like these, RID to assess an individual's vitamin A status should be done at 21-28 d after isotope dosing.

Background Previous compartmental models describing and quantifying whole-body vitamin A (VA) metabolism have been developed from plasma retinol kinetic data after human subjects ingest stable isotope-labeled VA. For humans, models based on data obtained from other sampling sites (e.g., excreta or milk) have not been proposed. Objectives Our objective was to determine whether comparable model predictions of VA total body stores (TBS) in theoretical lactating women were obtained using tracer data from only retinol in plasma or VA in milk. Methods We used Simulation, Analysis and Modeling software to simulate values for TBS and the coefficients used in the retinol isotope dilution (RID) equation TBS = FaS/SA(p) (Fa, fraction of dose in stores; S, retinol specific activity (SA) in plasma/SA in stores; SA(p), specific activity in plasma). We compared individual subject predictions of TBS and FaS based on modeling only plasma or only milk tracer data to previous results ("assigned values") for 12 theoretical lactating women when modeling was done based on tracer data for chylomicron retinyl esters, plasma retinol, and milk VA. Results For subjects with a wide range of TBS, model-predicted TBS based on only plasma data were comparable with assigned values (range: 94%-106%). Using only milk data, predictions ranged from 72% to 178%, but when VA intake was included in modeling, predictions were improved (97%-102%). Similar results were obtained for simulated FaS. Conclusions If confirmed in free-living lactating women, results indicate that, similar to models based on serial plasma sampling, a model for whole-body VA kinetics, including predictions of TBS and FaS, can be identified based on tracer data for VA in milk when VA intake is included as a modeling constraint. Milk data have not been previously used for compartmental modeling of VA in humans.

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. Objectives: Objectives were to identify sampling times that provide accurate estimates of TBS by RID in groups and individuals by applying compartmental modeling to data for theoretical adults and children. Methods: We selected previously generated hypothetical adults and children (20 per group) that had a wide range of assigned values for TBS and vitamin A kinetic parameters. We used the Simulation, Analysis and Modeling software to simulate individual kinetic responses; then we calculated geometric mean values for the RID equation coefficients and each individual's plasma retinol specific activity at various times, using those values to predict group mean and individual subject TBS. Predicted values for TBS were compared with assigned values. Results: Accurate estimates of group mean TBS were obtained at all sampling times from 1 to 30 d in both adults and children. For individuals, correlations between RID-predicted TBS and assigned values increased with time in the adults (R-2 = 0.80 at day 14, 0.96 at day 21, and 0.99 at day 28); a similar trend was observed for the children, with R-2 = 0.82 at day 7 and increasing to 0.97 at days 21 and 28 (P < 0.001 for all comparisons). Conclusions: Although no single, unique time provided the most accurate prediction of TBS for all individuals within these groups, applying the RID method at 21 or 28 d yielded predictions that were within 25% of assigned values for 90% or 95% of adults, respectively; corresponding values for children were 80% from 10 to 20 d, and 85% at 21 and 28 d. For most subjects, early times (<14 d for adults and <10 d for children) provided less accurate predictions.

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). Using individual SAp and group geometric mean FaS values from 1-28 d, we calculated individual and group mean TBS and compared them to assigned values. RESULTS Mean TBS was accurately predicted for both groups at all times. For individuals, predicted and assigned TBS were closest when the CV% for FaS was low [12-14%; 4-13 d (low), 12-28 d (high)]. The mean percentage error for TBS was <10% from 2-19 d (low) and 7-28 d (high). Predicted TBS was within 25% of assigned TBS for ≥80% of children from 3-23 d (low) and 9-28 d (high). Within groups, RID tended to overestimate lower TBS and underestimate higher TBS. CONCLUSIONS Using a good estimate for FaS, accurate RID predictions of TBS for individuals will be obtained at many times. If vitamin A status is low, results indicate that early sampling (e.g., 4-13 d) is optimal; if vitamin A status is high, sampling at 12-28 d is indicated. When vitamin A status is unknown, sampling at 14 d is recommended, or a super-subject design can be used to obtain the group mean FaS at various times for RID prediction of TBS in individuals.

Given that combined vitamin A (VA) and retinoic acid (RA) supplementation stimulated the intestinal uptake of plasma retinyl esters in neonatal rats, we administrated an RA dose as a pretreatment before VA supplementation to investigate the distinct effect of RA on intestinal VA kinetics. On postnatal days (P) 2 and 3, half of the pups received an oral dose of RA (RA group), while the remaining received canola oil as the control (CN). On P4, after receiving an oral dose of 3H-labeled VA, pups were euthanized at selected times (n = 4–6/treatment/time) and intestine was collected. In both CN and RA groups, intestinal VA mass increased dramatically after VA supplementation; however, RA-pretreated pups had relatively higher VA levels from 10 h and accumulated 30% more VA over the 30-h study. Labeled VA rapidly peaked in the intestine of CN pups and then declined from 13 h, while a continuous increase was observed in the RA group, with a second peak at 10 h and nearly twice the accumulation of 3H-labeled VA compared to CN. Our findings indicate that RA pretreatment may stimulate the influx of supplemental VA into the intestine, and the increased VA accumulation suggests a potential VA storage capacity in neonatal intestine.

BACKGROUND:Vitamin A (VA) plays critical roles in prenatal and postnatal development; however, limited information is available regarding maternal VA metabolism during pregnancy and lactation.OBJECTIVES:We investigated the impact of pregnancy and lactation on VA metabolism and kinetics in rats, hypothesizing that changes in physiological status would naturally perturb whole-body VA kinetics.METHODS:Eight-week old female rats (n = 10) fed an AIN-93G diet received an oral tracer dose of 3H-labeled retinol to initiate the kinetic study. On d 21 after dosing, six female rats were mated. Serial blood samples were collected from each female rat at selected times after dose administration until d 14 of lactation. Model-based compartmental analysis was applied to the plasma tracer data to develop VA kinetic models.RESULTS:Our compartmental model revealed that pregnancy resulted in a gradual increase in hepatic VA mobilization, presumably to support different stages of fetal development. Additionally, the model indicates that during lactation, VA derived from dietary intake was the primary source of VA delivered to the mammary gland for milk VA secretion.CONCLUSION:During pregnancy and lactation in rats with an adequate VA intake and previous VA storage, the internal redistribution of VA and increased uptake from diet supported the maintenance of VA homeostasis.