08/28/2023 - Role of transporters in drug ADME New

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

John D Clarke 1 2, Sabrina M Judson 1, Dan-Dan Tian 1, Trevor O Kirby 1, Rakshit S Tanna 1, Adrienn Matula-Péntek 3, Miklós Horváth 3, Matthew E Layton 4, John R White 5, Nadja B Cech 6, Kenneth E Thummel 2 7, Jeannine S McCune 2 8, Danny D Shen 2 7, Mary F Paine 1 2

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PMID: 37639334 PMCID: PMC10582660 DOI: 10.1111/cts.13578

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Abstract

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 (Ki ~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 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 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.

© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

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