Co‐consuming green tea with raloxifene decreases raloxifene systemic exposure in healthy adult participants

Green tea is a popular beverage worldwide. The abundant green tea catechin (−)‐epigallocatechin gallate (EGCG) is a potent in vitro inhibitor of intestinal UDP‐glucuronosyltransferase (UGT) activity (K ( i ) ~2 μM). Co‐consuming green tea with intestinal UGT drug substrates, including raloxifene, could increase systemic drug exposure. The effects of a well‐characterized green tea on the pharmacokinetics of raloxifene, raloxifene 4′‐glucuronide, and raloxifene 6‐glucuronide were evaluated in 16 healthy adults via a three‐arm crossover, fixed‐sequence study. Raloxifene (60 mg) was administered orally with water (baseline), with green tea for 1 day (acute), and on the fifth day after daily green tea administration for 4 days (chronic). Unexpectedly, green tea decreased the geometric mean green tea/baseline raloxifene AUC(0–96h) ratio to ~0.60 after both acute and chronic administration, which is below the predefined no‐effect range (0.75–1.33). Lack of change in terminal half‐life and glucuronide‐to‐raloxifene ratios indicated the predominant mechanism was not inhibition of intestinal UGT. One potential mechanism includes inhibition of intestinal transport. Using established transfected cell systems, a green tea extract normalized to EGCG inhibited 10 of 16 transporters tested (IC(50), 0.37–12 μM). Another potential mechanism, interruption by green tea of gut microbe‐mediated raloxifene reabsorption, prompted a follow‐up exploratory clinical study to evaluate the potential for a green tea–gut microbiota–drug interaction. No clear mechanisms were identified. Overall, results highlight that improvements in current models and methods used to predict UGT‐mediated drug interactions are needed. Informing patients about the risk of co‐consuming green tea with raloxifene may be considered.