Physiologically based pharmacokinetic modeling of tea catechin mixture in rats and humans.

Francis C P Law,Stephen Lam,Meicun Yao,Hui-Chang Bi

doi:10.1002/prp2.305

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.

Highlights

Green tea (GT), the water extract of Camellia sinensis leaves, consists of a complex mixture of tea catechins (TCs) such as epigallocatechin gallate (EGCg), epigallocatechin (EGC), epicatechin gallate (ECg), and epicatechin (EC) (Fig. 1)
A physiologically based pharmacokinetic (PBPK) model of EGCg was developed by comparing model simulation with free EGCg concentration-time data in the plasma of rats after consuming 2500 mg/kg of crude EGCg in Polyphenon E (PE) (Zhu et al 2000)
Well as total EGCg (Fig. 5) in the plasma of rats. This is unexpected since the PBPK model supposedly is predictive for the kinetics of free EGCg only

Summary

Introduction

Green tea (GT), the water extract of Camellia sinensis leaves, consists of a complex mixture of tea catechins (TCs) such as epigallocatechin gallate (EGCg), epigallocatechin (EGC), epicatechin gallate (ECg), and epicatechin (EC) (Fig. 1). Consumption of GT is believed to be beneficial to health including prevention of cancer, obesity, diabetes, and cardiovascular diseases (Saito et al 2009). Polyphenon E (PE), a standardized GT extract, has been found an effective agent in slowing down the progression of early stage cancer in humans (Shanafelt et al 2013). TCs may cause toxic effects in animals and humans especially when they are administered at high doses, that is, 10–29 mg/kg/day tea-based diets (Lambert et al 2007). The pharmacokinetics (PKs) and tissue distribution of TCs have been studied in different animal species including rodents (Chen et al 1997; Suganuma et al 1998; Zhu et al 2000; Cai et al 2002), dogs (Swezey et al 2003), and humans (Pietta et al 1998; Chow et al 2001; Van Amelsvoort et al 2001; Lee et al 2002; Meng et al 2002)

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