Co-consuming green tea with raloxifene decreases raloxifene systemic exposure in healthy adult participants
CTS-CLINICAL AND TRANSLATIONAL SCIENCE(2023)
摘要
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 similar to 2 mu M). 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 AUC0-96h 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 (IC50, 0.37-12 mu M). 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. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? The natural product green tea has been studied extensively as a precipitant of cytochrome P450 (CYP)-mediated and organic anion transporting polypeptide (OATP)-mediated drug interactions, but potential interactions involving other pathways, such as the UDP-glucuronosyltransferases (UGTs), have not been investigated in humans. A mechanistic static model predicted two abundant catechins in green tea would increase the area under the plasma concentration versus time curve of the intestinal UGT substrate raloxifene by up to six-fold relative to baseline. WHAT QUESTION DID THIS STUDY ADDRESS? Does the in vitro-in vivo prediction translate to human participants? Do mechanisms underlying the pharmacokinetic green tea-raloxifene interaction involve intestinal transporters and/or the gut microbiota? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Green tea precipitated a pharmacokinetic interaction with raloxifene that was opposite to the predicted effect, indicating the overarching mechanism does not involve inhibition of intestinal UGTs. Results implicated one or more processes involved in intestinal absorption. MRP3 was the only transporter identified that may contribute to the interaction. An exploratory follow-up clinical study suggested green tea did not interrupt raloxifene enterohepatic recycling through inhibition of bacterial beta-glucuronidase activity. The preexisting gut microbiota may interact with green tea to influence raloxifene stool recovery. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? CYP-based mechanistic static models used to predict pharmacokinetic interactions involving UGTs with improved predictive performance are needed. Health care providers may consider informing their patients about potential risks when co-consuming green tea with raloxifene.
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