The purpose of this study was to examine the pharmacokinetics of quercetin aglycone as well as its conjugated metabolites and to develop a population pharmacokinetic model for quercetin that incorporates enterohepatic recirculation. The stability of quercetin in different matrices at various temperatures and pH, and the quercetin content of six capsules of the herbal preparation Quercetin-500 Plus were determined by HPLC. Subjects received quercetin 500 mg three times daily and blood and urine samples were obtained. The concentration of quercetin aglycone and conjugated metabolites were assayed using a liquid chromatography-tandem mass spectrometry assay. Pharmacokinetic parameters were determined using noncompartmental analysis with WinNonlin. A population compartment model incorporating input from the gallbladder was developed to account for the enterohepatic recirculation observed with quercetin. The oral clearance (CL/F) was high (3.5 x 10(4)l/h) with an average terminal half-life of 3.5 h for quercetin. The plasma concentration versus time curves exhibited re-entry peaks. A one-compartment model that included enterohepatic recirculation best described the plasma data. This represents the first comprehensive evaluation of the pharmacokinetics and enterohepatic recirculation of quercetin in humans. Population pharmacokinetic models adapted for enterohepatic recirculation allowed an assessment of the magnitude and frequency of the enterohepatic recirculation process.