Compartmental Modeling of Vitamin A Stable Isotope Data from Milk or Plasma Provides Comparable Predictions of Vitamin A Stores in Theoretical Lactating Women.

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/SAp (Fa, fraction of dose in stores; S, retinol specific activity (SA) in plasma/SA in stores; SAp, 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.

Development of a Compartmental Model for Studying Vitamin A Kinetics and Status in Theoretical Lactating Women.

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.

Kinetic analysis shows that vitamin A disposal rate in humans is positively correlated with vitamin A stores.

Vitamin A (VA) kinetics, storage, and disposal rate were determined in well-nourished Chinese and U.S. adults using model-based compartmental analysis. [(2)H(8)]Retinyl acetate (8.9 micromol) was orally administered to U.S. (n = 12; 59 +/- 9 y; mean +/- SD) and Chinese adults (n = 14; 54 +/- 4 y) and serum tracer and VA concentrations were measured from 3 h to 56 d. Using the Windows version of the Simulation, Analysis and Modeling software, we determined that the average time from dosing until appearance of labeled retinol in serum was greater in U.S. subjects (40.6 +/- 8.47 h) than in Chinese subjects (32.2 +/- 5.84 h; P < 0.01). Model-predicted total traced mass (898 +/- 637 vs. 237 +/- 109 micromol), disposal rate (14.7 +/- 5.87 vs. 5.58 +/- 2.04 micromol/d), and system residence time (58.9 +/- 28.7 vs. 42.9 +/- 14.6 d) were greater in U.S. than in Chinese subjects (P < 0.05). The model-predicted VA mass and VA mass estimated by deuterated retinol dilution at 3 and 24 d did not differ. VA disposal rate was positively correlated with VA traced mass in Chinese (R(2) = 0.556), U.S. (R(2) = 0.579), and all subjects (R(2) = 0.808). Additionally, VA disposal rate was significantly correlated with serum retinol pool size (R(2) = 0.227) and retinol concentration (R(2) = 0.330) in all subjects. Our results support the hypothesis that VA stores are the principle determinant of VA disposal rate in healthy, well-nourished adults.

Model-based compartmental analysis indicates a reduced mobilization of hepatic vitamin A during inflammation in rats.

Vitamin A (VA) kinetics was studied in rats with marginal VA stores before, during, and after inflammation. Rats received orally [11,12-(3)H(N)]retinol ([(3)H]VA; day 0), and inflammation was induced on day 21 with lipopolysacchride (LPS) for 3 days (n = 5) or recombinant human interleukin-6 (rhIL-6) for 7 days (n = 5). Both the fraction of [(3)H]VA and retinol concentrations in plasma were reduced significantly by LPS or rhIL-6. Compartmental analysis using the Windows version of Simulation, Analysis, and Modeling software was applied to group mean data, and non-steady-state models were developed. After absorption, VA kinetics was described by a three-compartment model that included plasma, kidney/interstitium, and liver/carcass. Four mechanisms decreasing plasma retinol were investigated: increased urinary excretion, increased irreversible loss, increased movement into interstitium, and decreased hepatic mobilization. Modeling demonstrated that a 79% reduction in hepatic mobilization of retinol (from 4.3 to 0.9 nmol/h) by 15 h after LPS best accounted for the observed changes in plasma VA kinetics (sum of squares = 9.05 x 10(-07)). rhIL-6 caused an earlier reduction (75% by 5.6 h). These models predicted a return to control values by 10 days after inflammation. If prolonged, inflammation-induced hyporetinolemia can render hepatic retinol unavailable to extrahepatic tissues, possibly leading to their impaired function, as observed in VA-deficient children with measles infection.