title: Milk Thistle Constituents Inhibit Raloxifene Intestinal Glucuronidation: A Potential Clinically Relevant Natural Product-Drug Interaction.
abstract: Women at high risk of developing breast cancer are prescribed selective estrogen response modulators, including raloxifene, as chemoprevention. Patients often seek complementary and alternative treatment modalities, including herbal products, to supplement prescribed medications. Milk thistle preparations, including silibinin and silymarin, are top-selling herbal products that may be consumed by women taking raloxifene, which undergoes extensive first-pass glucuronidation in the intestine. Key constituents in milk thistle, flavonolignans, were previously shown to be potent inhibitors of intestinal UDP-glucuronosyl transferases (UGTs), with IC50s ≤ 10 μM. Taken together, milk thistle preparations may perpetrate unwanted interactions with raloxifene. The objective of this work was to evaluate the inhibitory effects of individual milk thistle constituents on the intestinal glucuronidation of raloxifene using human intestinal microsomes and human embryonic kidney cell lysates overexpressing UGT1A1, UGT1A8, and UGT1A10, isoforms highly expressed in the intestine that are critical to raloxifene clearance. The flavonolignans silybin A and silybin B were potent inhibitors of both raloxifene 4'- and 6-glucuronidation in all enzyme systems. The Kis (human intestinal microsomes, 27-66 µM; UGT1A1, 3.2-8.3 µM; UGT1A8, 19-73 µM; and UGT1A10, 65-120 µM) encompassed reported intestinal tissue concentrations (20-310 µM), prompting prediction of clinical interaction risk using a mechanistic static model. Silibinin and silymarin were predicted to increase raloxifene systemic exposure by 4- to 5-fold, indicating high interaction risk that merits further evaluation. This systematic investigation of the potential interaction between a widely used herbal product and chemopreventive agent underscores the importance of understanding natural product-drug interactions in the context of cancer prevention.
authors.affiliation: Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., A.G.V., P.L.), College of Pharmacy, Washington State University, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, North Carolina (N.H.O.).
authors.forename: Brandon T
authors.initials: BT
authors.lastname: Gufford
authors.affiliation: Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., A.G.V., P.L.), College of Pharmacy, Washington State University, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, North Carolina (N.H.O.).
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., A.G.V., P.L.), College of Pharmacy, Washington State University, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, North Carolina (N.H.O.).
authors.forename: Ana G
authors.initials: AG
authors.lastname: Vergara
authors.affiliation: Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., A.G.V., P.L.), College of Pharmacy, Washington State University, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, North Carolina (N.H.O.).
authors.forename: Philip
authors.initials: P
authors.lastname: Lazarus
authors.affiliation: Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., A.G.V., P.L.), College of Pharmacy, Washington State University, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, North Carolina (N.H.O.).
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Oberlies
authors.affiliation: Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., A.G.V., P.L.), College of Pharmacy, Washington State University, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, North Carolina (N.H.O.) mary.paine@wsu.edu.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Paine
mesh_terms: D001943:Breast Neoplasms / Q000517:prevention & control; D004347:Drug Interactions; D005260:Female; D020719:Glucuronides / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D020944:Silybum marianum / Q000737:chemistry*; D020849:Raloxifene Hydrochloride / Q000378:metabolism* / Q000627:therapeutic use; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D020719:Glucuronides; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride