Compartmental and noncompartmental modeling of ¹³C-lycopene absorption, isomerization, and distribution kinetics in healthy adults

Abstract

Background: Lycopene, which is a red carotenoid in tomatoes, has been hypothesized to mediate disease-preventive effects associated with tomato consumption. Lycopene is consumed primarily as the all-trans geometric isomer in foods, whereas human plasma and tissues show greater proportions of cis isomers.

Objective: With the use of compartmental modeling and stable isotope technology, we determined whether endogenous all-trans-to-cis-lycopene isomerization or isomeric-bioavailability differences underlie the greater proportion of lycopene cis isomers in human tissues than in tomato foods.

Design: Healthy men (n = 4) and women (n = 4) consumed (13)C-lycopene (10.2 mg; 82% all-trans and 18% cis), and plasma was collected over 28 d. Unlabeled and (13)C-labeled total lycopene and lycopene-isomer plasma concentrations, which were measured with the use of high-performance liquid chromatography-mass spectrometry, were fit to a 7-compartment model.

Results: Subjects absorbed a mean ± SEM of 23% ± 6% of the lycopene. The proportion of plasma cis-(13)C-lycopene isomers increased over time, and all-trans had a shorter half-life than that of cis isomers (5.3 ± 0.3 and 8.8 ± 0.6 d, respectively; P < 0.001) and an earlier time to reach maximal plasma concentration than that of cis isomers (28 ± 7 and 48 ± 9 h, respectively). A compartmental model that allowed for interindividual differences in cis- and all-trans-lycopene bioavailability and endogenous trans-to-cis-lycopene isomerization was predictive of plasma (13)C and unlabeled cis- and all-trans-lycopene concentrations. Although the bioavailability of cis (24.5% ± 6%) and all-trans (23.2% ± 8%) isomers did not differ, endogenous isomerization (0.97 ± 0.25 μmol/d in the fast-turnover tissue lycopene pool) drove tissue and plasma isomeric profiles.

Conclusion: (13)C-Lycopene combined with physiologic compartmental modeling provides a strategy for following complex in vivo metabolic processes in humans and reveals that postabsorptive trans-to-cis-lycopene isomerization, and not the differential bioavailability of isomers, drives tissue and plasma enrichment of cis-lycopene. This trial was registered at clinicaltrials.gov as NCT01692340.

Keywords: compartmental modeling; isomers; kinetics; lycopene; tracers.

© 2015 American Society for Nutrition.

Figures

FIGURE 1

Structure of lycopene (A), representative chromatogram of 13C-lycopene monitored at 470 nm (B), and the calculated 13C-isotopologue distribution in 13C-lycopene used for dosing (C). The percentage of isotopologue abundance was calculated from mass chromatogram peak areas of all-E + 5-Z-lycopene isotopologues masses from an m/z = 535.5 (the mass of unlabeled lycopene + 1 mass unit for H+ as a result of the analysis being conducted in positive ion mode) to m/z = 577.5 (the mass of uniformly labeled 13C-lycopene + 1 mass unit for H+ as a result of the analysis being conducted in positive ion mode). AU, arbitrary units.

FIGURE 2

Conceptual compartmental pharmacokinetic model of total lycopene absorption, distribution, and clearance on the basis of Diwadkar-Navsariwala et al. (32). Ovals represent kinetically homogeneous, physiologic compartments. The empirically measured plasma compartment within the plasma compartment is delineated by a dashed rectangle. The rectangle enclosing “Gastric Motility Delay” represents a delay element to account for the interindividual variability in the time between ingestion and plasma appearance. 13C-lycopene tracer introduction is denoted by an asterisk, bold numbers inside ovals represent compartment numbers used in the compartmental analysis, italicized lettering next to arrows represents the L(I,J), which is the fractional transfer coefficient, used in the model development to describe the rate of transfer between compartments for the transfer of lycopene from compartment J to compartment I. GI, gastrointestinal.

FIGURE 3

Final compartmental model describing all-trans and cis-lycopene absorption, distribution, isomerization, and clearance kinetics. Ovals represent kinetically homogeneous, physiologic compartments. The empirically measured plasma values represent the sum of 2 model compartments as delineated by the dashed rectangles. The solid rectangles enclosing “Gastric Motility Delay” represent a delay element to account for interindividual variability in the time between ingestion and plasma appearance. 13C-lycopene introduction to the system is denoted by the arrows connecting “cis-lycopene” and “all-trans-lycopene” with the GI tract compartment, bold numbers inside ovals represent the compartment number used in compartmental analysis, and italicized lettering next to arrows represents the L(I,J), which is the fractional transfer coefficient, used in model development to describe the rate of transfer between compartments for the transfer of lycopene from compartment J to compartment I. GI, gastrointestinal.

FIGURE 4

Mean ± SEM (n = 8) plasma 13C-lycopene and native lycopene concentrations. (A) Extracted ion chromatogram at an m/z of 576.57 showing plasma 13C-lycopene isomers. (B) Plasma native lycopene, 13C-lycopene, and total (summed native and 13C-lycopene) lycopene concentrations over 72 h. (C) Average, highest, and lowest plasma lycopene mass responses over 672 h. 13C-lycopene isomer concentrations over 24 (D) and 672 (E) h are shown.

FIGURE 5

Example of total lycopene compartmental model–predicted fraction of tracer dose in plasma (A) and mass of tracee lycopene in plasma (B) in a representative subject. The solid line represents the model-predicted tracer and tracee amounts, and the solid triangles represent the empirically measured amounts. Also shown are the population averages for the fraction of the 13C-lycopene dose in the total plasma compartment (C), fast-turnover (D) and slow-turnover (E) tissue lycopene pools, and the mass of tracee lycopene in the plasma (F) over 28 d after a single oral 13C-lycopene dose.

FIGURE 6

Lycopene isomer compartmental model–predicted fractions of dose in the plasma (A), fast-turnover (B) and slow-turnover (C) tissue lycopene pools, and model-predicted mass of tracee lycopene in plasma (D) over 28 d after a single oral 13C-lycopene dose and during controlled dietary lycopene intakes. All-trans lycopene is marked with a dashed line and total cis-lycopene with a solid line. The inset in panel A is an enlargement of the 0–3-d fraction of dose in plasma data.