Determination of human FF of polyphenols using allometric scaling.

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 (FF), is calculated by dividing bioavailability (F) by hepatic availability (F), and F is obtained from pharmacokinetic data from both intravenous (i.v.) and oral (p.o.) administration. However, human FF of polyphenols is hardly reported, as human i.v. data are extremely scarce. In this study, we developed an estimation method for FF of polyphenols in humans based on the extrapolation of rat clearance using allometric scaling (allometric scaling-based FF calculation method, AS- FFCM). First, for quercetin, for which human i.v. data have been reported, we compared the FF obtained by AS-FFCM 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 FF of structurally diverse polyphenols (genistein, baicalein, resveratrol, and epicatechin) using AS-FFCM, 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-FFCM to focus on their excretion. The FF value of naringenin was obtained using modified AS-FFCM 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.