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

• Published in: Drug metabolism and disposition Vol. 46; no. 5; pp. 552 - 560
• Main Authors: Tian, Dan-Dan, Kellogg, Joshua J, Okut, Neşe, Oberlies, Nicholas H, Cech, Nadja B, Shen, Danny D, McCune, Jeannine S, Paine, Mary F
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics, Inc 01-05-2018; The American Society for Pharmacology and Experimental Therapeutics
• Subjects: Beverages; Bioassays; Biochemistry; Camellia sinensis; Camellia sinensis - chemistry; Catechin; Catechin - analogs & derivatives; Catechin - pharmacology; Constituents; Drug Interactions - physiology; Dynamic models; Epicatechin; Epigallocatechin gallate; Estrogen receptors; Evaluation; Extrapolation; Glucuronosyltransferase; Glucuronosyltransferase - antagonists & inhibitors; Glucuronosyltransferase - metabolism; Green tea; Humans; Hymecromone - pharmacology; In vitro methods and tests; In vivo methods and tests; Inhibition; Inhibitors; Intestinal Mucosa - metabolism; Intestine; Intestines - drug effects; Microsomes; Microsomes - drug effects; Microsomes - metabolism; Natural products; Plant Extracts - pharmacology; Raloxifene; Raloxifene Hydrochloride - pharmacology; Static models; Substrates; Tea; Tea - chemistry; UDP-glucuronosyltransferase
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.117.079491

Green tea (
) 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
g/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 and (-)-epigallocatechin gallate showed concentration-dependent inhibition, with IC
values (105 and 59
M, respectively) near or below concentrations measured in a cup (240 ml) of tea (66 and 240
M, respectively). Using the clinical intestinal UGT substrate raloxifene, the
values were ∼1.0 and 2.0
M, 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.