Kinetic disposition of dietary polyphenols and methylxanthines in the rat mammary tissue

We recently showed that methylxanthines and conjugated phenolic-derived metabolites reached the mammary tissue (MT) of breast cancer patients after consuming a blend of phenolic-rich extracts. The pre-surgery fasting could prevent the detection of some (including those non-conjugated) metabolites. We investigated here the pharmacokinetics in rat plasma and MT of phenolic-derived metabolites and methylxanthines using the same blend (pomegranate, olive, cocoa, orange, lemon, and grapeseed extracts plus resveratrol; containing 37 phenolics, theobromine, and caffeine). We also compared the pharmacokinetics of resveratrol when administered in the blend or individually. We show for the first time that micromolar levels of methylxanthines and conjugated-derived (but not free) metabolites from resveratrol, dihydroresveratrol, hesperetin, urolithins, and hydroxytyrosol reached the MT. Resveratrol-3-glucuronide and resveratrol-3-sulfate showed shorter Tmax (plasma and MT) and resveratrol-3-sulfate higher Cmax (MT) when resveratrol was administered individually. This study could help to conveniently design preclinical studies using physiologically relevant conditions in (breast) cell models.