Drug Metabolism and Disposition 2014-10-01

Identification of diet-derived constituents as potent inhibitors of intestinal glucuronidation.

Brandon T Gufford, Gang Chen, Philip Lazarus, Tyler N Graf, Nicholas H Oberlies, Mary F Paine

文献索引：Drug Metab. Dispos. 42(10) , 1675-83, (2014)

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摘要

Drug-metabolizing enzymes within enterocytes constitute a key barrier to xenobiotic entry into the systemic circulation. Furanocoumarins in grapefruit juice are cornerstone examples of diet-derived xenobiotics that perpetrate interactions with drugs via mechanism-based inhibition of intestinal CYP3A4. Relative to intestinal CYP3A4-mediated inhibition, alternate mechanisms underlying dietary substance-drug interactions remain understudied. A working systematic framework was applied to a panel of structurally diverse diet-derived constituents/extracts (n = 15) as inhibitors of intestinal UDP-glucuronosyl transferases (UGTs) to identify and characterize additional perpetrators of dietary substance-drug interactions. Using a screening assay involving the nonspecific UGT probe substrate 4-methylumbelliferone, human intestinal microsomes, and human embryonic kidney cell lysates overexpressing gut-relevant UGT1A isoforms, 14 diet-derived constituents/extracts inhibited UGT activity by >50% in at least one enzyme source, prompting IC(50) determination. The IC(50) values of 13 constituents/extracts (≤10 μM with at least one enzyme source) were well below intestinal tissue concentrations or concentrations in relevant juices, suggesting that these diet-derived substances can inhibit intestinal UGTs at clinically achievable concentrations. Evaluation of the effect of inhibitor depletion on IC(50) determination demonstrated substantial impact (up to 2.8-fold shift) using silybin A and silybin B, two key flavonolignans from milk thistle (Silybum marianum) as exemplar inhibitors, highlighting an important consideration for interpretation of UGT inhibition in vitro. Results from this work will help refine a working systematic framework to identify dietary substance-drug interactions that warrant advanced modeling and simulation to inform clinical assessment.Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.