Determination of human F_aF_g of polyphenols using allometric scaling

Abstract

Certain polyphenols exhibit low permeability; precise prediction of their intestinal absorption is important for understanding internal exposure in humans. Intestinal availability, which represents the fraction of administered compounds that reach the portal blood (F_aF_g), is calculated by dividing bioavailability (F) by hepatic availability (F_h), and F is obtained from pharmacokinetic data from both intravenous (i.v.) and oral (p.o.) administration. However, human F_aF_g of polyphenols is hardly reported, as human i.v. data are extremely scarce. In this study, we developed an estimation method for F_aF_g of polyphenols in humans based on the extrapolation of rat clearance using allometric scaling (allometric scaling-based F_aF_g calculation method, AS- F_aF_gCM). First, for quercetin, for which human i.v. data have been reported, we compared the F_aF_g obtained by AS-F_aF_gCM with the traditional approach using human i.v. and p.o. data. Less than two-fold difference in FaFg values was observed between the two approaches. Next, we obtained F_aF_g of structurally diverse polyphenols (genistein, baicalein, resveratrol, and epicatechin) using AS-F_aF_gCM, demonstrating that all of them were poorly absorbable. Furthermore, to utilize the pharmacokinetic data of the total concentration, including aglycones and metabolites, we modified the AS-F_aF_gCM to focus on their excretion. The F_aF_g value of naringenin was obtained using modified AS-F_aF_gCM and was nearly equal to that of baicalein, a structural isomer of naringenin. This study provides quantitative information on the intestinal absorption of polyphenols using comprehensive estimation methods.