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Physiologically Based Pharmacokinetic Modeling of Tea Catechin Mixture in Rats and Humans

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Physiologically Based Pharmacokinetic Modeling of Tea Catechin Mixture in Rats and Humans

Francis C P Law et al. Pharmacol Res Perspect.

Abstract

Although green tea (Camellia sinensis) (GT) contains a large number of polyphenolic compounds with anti-oxidative and anti-proliferative activities, little is known of the pharmacokinetics and tissue dose of tea catechins (TCs) as a chemical mixture in humans. The objectives of this study were to develop and validate a physiologically based pharmacokinetic (PBPK) model of tea catechin mixture (TCM) in rats and humans, and to predict an integrated or total concentration of TCM in the plasma of humans after consuming GT or Polyphenon E (PE). To this end, a PBPK model of epigallocatechin gallate (EGCg) consisting of 13 first-order, blood flow-limited tissue compartments was first developed in rats. The rat model was scaled up to humans by replacing its physiological parameters, pharmacokinetic parameters and tissue/blood partition coefficients (PCs) with human-specific values. Both rat and human EGCg models were then extrapolated to other TCs by substituting its physicochemical parameters, pharmacokinetic parameters, and PCs with catechin-specific values. Finally, a PBPK model of TCM was constructed by linking three rat (or human) tea catechin models together without including a description for pharmacokinetic interaction between the TCs. The mixture PBPK model accurately predicted the pharmacokinetic behaviors of three individual TCs in the plasma of rats and humans after GT or PE consumption. Model-predicted total TCM concentration in the plasma was linearly related to the dose consumed by humans. The mixture PBPK model is able to translate an external dose of TCM into internal target tissue doses for future safety assessment and dose-response analysis studies in humans. The modeling framework as described in this paper is also applicable to the bioactive chemical in other plant-based health products.

Keywords: PBPK model; systemic dosimetry; tea catechins.

Figures

Figure 1
Figure 1
Chemical structures of EGCg, EGC, ECg, and EC.
Figure 2
Figure 2
Schematic for the physiologically based pharmacokinetic description of a tea catechin in rats and humans. CA, CV, and Q, respectively, represent arterial concentrations, venous concentrations, and blood flows. The symbols and pharmacokinetic parameters are defined in the Appendix, and Tables 2, 4. The entero‐hepatic recycling sub‐model was adapted from Harrison and Gibaldi (1977) with modification.
Figure 3
Figure 3
Schematic for the physiologically based pharmacokinetic description of a mixture of tea catechins in rats and humans. CA, CV, and Q, respectively, represent arterial concentrations, venous concentrations and blood flows. The symbols and pharmacokinetic parameters are defined in the Appendix, and Tables 2, 4. The entero‐hepatic recycling sub‐model was adapted from Harrison and Gibaldi (1977) with modification. For the sake of clarity, only the parameters of a single TC was shown in the enterohepatic recycling sub‐model.
Figure 4
Figure 4
Predicted and measured time course of free EGCg concentrations in the plasma of rats after consuming a single dose of 2500 mg/kg crude EGCg from a PE preparation. ▄ represents mean concentrations of free EGCg (N = 6) at different time points post‐dosing (Zhu et al. 2000). _________ represents model‐simulated concentration‐time curve of free EGCg.
Figure 5
Figure 5
Predicted and measured EGCg concentrations in the plasma of rats after consuming a single dose of pure EGCg (75 mg/kg) or crude EGCg (14.6 mg/kg) from a PE formulation. ▄ and ● represent the time course of total EGCg (free EGCg plus conjugated forms) concentrations in the plasma of rats after consuming pure EGCg and crude EGCG, respectively (Chen et al. 1997). __________ represents model‐simulated concentration‐time curve of free EGCg in the plasma of rats after consuming pure EGCg (upper curve) or crude EGCg (lower curve).
Figure 6
Figure 6
Predicted and measured free EGCg concentrations in the plasma of humans after consuming a single dose of 400 mg pure EGCg. ▄ represents mean concentrations of free EGCg (N = 8) at different time points post‐dosing (Chow et al. 2003). __________ represents model‐simulated concentration‐time curve for free EGCg.
Figure 7
Figure 7
Predicted and measured free EGCg concentrations in the plasma of humans after consuming 400 mg pure EGCg or 400 mg crude EGCg from a PE formulation. ▄ and ● represent mean concentrations of free EGCg (N = 5) in the plasma of humans after consuming pure EGCg and crude EGCg, respectively (Chow et al. 2001). ___________ represents the simulated concentration‐time curves of humans after consuming pure EGCg or crude EGCg; these curves are identical because both EGCg formulations contain the same amount (400 mg) of EGCg (Chow et al. 2001),
Figure 8
Figure 8
Predicted and measured free EGCg, ECg, and EC concentrations in the plasma of rats after consuming PE containing a mixture of EGCg (2500 mg/kg), ECg (650 mg/kg), and EC (250 mg/kg). ▄, ♦, and ●, respectively, represent mean concentrations (N = 6) of free EGCg, ECg, and EC at different time points post‐dosing (Zhu et al. 2000). ___________ represents model‐simulated concentration‐time curves for free EGCg (top), ECg, (middle), and EC (bottom). Note: the EGCg concentration‐time curve is taken directly from Figure 4 for comparison.
Figure 9
Figure 9
Predicted and measured free EGCg, EGC, and EC concentrations in the plasma of humans after consuming PE containing a mixture of EGCg (8.3 mg/kg), EGC (1.54 mg/kg), and EC (1.29 mg/kg). ▄, ♦, and ●, respectively, represent mean plasma concentrations (N = 5) of EGCg, EGC, and EC at different time points post‐dosing (Chow et al. 2001); __________ represents model‐simulated concentration‐time curves for free EGCg (top), EGC (middle), and EC (bottom).
Figure 10
Figure 10
Predicted and measured free EGCg, EGC, and EC concentrations in the plasma of humans after consuming green tea solids containing a mixture of EGCg (2.78 mg/kg), EGC (2.20 mg/kg), and EC (0.64 mg/kg). ♦, ▄, and ●, respectively, represent mean plasma concentrations (N = 5) of EGCg, EGC, and EC at different time points post‐dosing (Lee et al. 2002). _______ represents model‐simulated concentration‐time curves for EGCg (top), EGC (middle), and EC (bottom).
Figure 11
Figure 11
Quantitative relationship between total TCM concentration in plasma and applied dose in humans. TCM dose metrics, expressed in μg EGCg equivalents/mL plasma or g of PE, are calculated using the concentration addition model of ATSDR (2004). ● represents total TCM concentrations in the plasma of humans after consuming 400, 800, or 1200 mg PE (Chow et al. 2005); ▲ and ▄ represent total TCM concentrations in the plasma of humans after consuming 20 mg/kg of green tea solids (Lee et al. 2002) and 600 mg of PE (Chow et al. 2001), respectively.

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