Identification of intestinal UDP-Glucuronosyltransferase inhibitors in green tea (Camellia sinensis) using a biochemometric approach: Application to raloxifene as a test drug via in vitro to in vivo extrapolation

Dan Dan Tian, Joshua J. Kellogg, Neşe Okut, Nicholas H. Oberlies, Nadja B. Cech, Danny D. Shen, Jeannine S. McCune, Mary F. Paine

Research output: Contribution to journalArticle

5 Scopus citations


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, (2)-epicatechin gallate and (2)-epigallocatechin gallate showed concentration-dependent inhibition, with IC50 values (105 and 59 μM, respectively) near or below concentrations measured in a cup (240 ml) of tea (66 and 240 μM, respectively). Using the clinical intestinal UGT substrate raloxifene, the Ki values 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 the 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.

Original languageEnglish (US)
Pages (from-to)552-560
Number of pages9
JournalDrug Metabolism and Disposition
Issue number5
StatePublished - May 2018


All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

Cite this