PT - JOURNAL ARTICLE AU - Dan-Dan Tian AU - Joshua J Kellogg AU - Neşe Okut AU - Nicholas H Oberlies AU - Nadja B Cech AU - Danny D Shen AU - Jeannine S McCune AU - Mary F Paine TI - Identification of Intestinal UDP-Glucuronosyltransferase Inhibitors in Green Tea (<em>Camellia sinensis</em>) Using a Biochemometric Approach: Application to Raloxifene as a Test Drug via In Vitro to In Vivo Extrapolation AID - 10.1124/dmd.117.079491 DP - 2018 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.117.079491 4099 - http://dmd.aspetjournals.org/content/early/2018/02/21/dmd.117.079491.short 4100 - http://dmd.aspetjournals.org/content/early/2018/02/21/dmd.117.079491.full AB - Green tea (Camellia sinensis) is a popular beverage worldwide, raising concern for adverse interactions when co-consumed with conventional drugs. Like many botanical natural products, green tea contains numerous polyphenolic constituents that undergo extensive glucuronidation. As such, the UDP-glucuronosyltransferases (UGTs), particularly intestinal UGTs, represent potential 'first-pass' targets for green tea-drug interactions. Candidate intestinal UGT inhibitors were identified using a biochemometrics approach, which combines bioassay and chemometric data. Extracts and fractions prepared from four widely consumed teas were screened (20-180 μg/mL) as inhibitors of UGT activity (4-methylumbelliferone glucuronidation) in human intestinal microsomes; all demonstrated concentration-dependent inhibition. A biochemometrics-identified fraction rich in UGT inhibitors from a representative tea was purified further and subjected to second-stage biochemometric analysis. Five catechins were identified as major constituents in the bioactive subfractions and prioritized for further evaluation. Of these catechins, (-)-epicatechin gallate (ECG) and (-)-epigallocatechin gallate (EGCG) showed concentration-dependent inhibition, with IC50s (105 and 59 μM, respectively) near or below concentrations measured in a cup (240 mL) of tea (66 and 240 μM, respectively). Using the clinically used intestinal UGT substrate raloxifene, Kis were ~1.0 and 2.0 μM, respectively. Using estimated intestinal lumen and enterocyte inhibitor concentrations, a mechanistic static model predicted green tea to increase raloxifene plasma area under the curve up to 6.1- and 1.3-fold, respectively. Application of this novel approach, which combines biochemometrics with in vitro-in vivo extrapolation, to other natural product-drug combinations will refine these procedures, informing the need for further evaluation via dynamic modeling and clinical testing.