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Drug Metab Dispos. 2018 May;46(5):552-560. doi: 10.1124/dmd.117.079491. Epub 2018 Feb 21.

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.

Author information

1
Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington (D.-D.T., M.F.P.); Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (J.J.K., N.O., N.H.O., N.B.C.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (D.D.S.); and Department of Population Sciences, City of Hope, Duarte, California (J.S.M.).
2
Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington (D.-D.T., M.F.P.); Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (J.J.K., N.O., N.H.O., N.B.C.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (D.D.S.); and Department of Population Sciences, City of Hope, Duarte, California (J.S.M.) mary.paine@wsu.edu.

Abstract

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 and (-)-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.

PMID:
29467215
PMCID:
PMC5890833
DOI:
10.1124/dmd.117.079491
[Indexed for MEDLINE]
Free PMC Article

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