Dmd059451 1675..1683
نویسندگان
چکیده
Drug-metabolizing enzymeswithin 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 UDPglucuronosyl 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 IC50 determination. The IC50 values of 13 constituents/extracts (£10 mMwith at least one enzyme source) were well below intestinal tissue concentrations or concentrations in relevant juices, suggesting that these dietderived substances can inhibit intestinal UGTs at clinically achievable concentrations. Evaluation of the effect of inhibitor depletion on IC50 determination demonstrated substantial impact (up to 2.8-fold shift) using silybin A and silybin B, two key flavonolignans from milk thistle (Silybummarianum) 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.
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2712463 (2013.01); HOJL 45104 (2013.01); HOJL 4511226 (2013.01); HOJL 4511233 (2013.01); HOJL 4511253 (2013.01); HOJL 451145 (2013.01); HOJL 4511608 (2013.01); HOJL 4511616 (2013.01); HOJL 4511675 (2013.01); HOJL 4511683 (2013.01); GllC 2013/0073 (2013.01); GllC 2213/33 (2013.01); GllC 2213/77 (2013.01) (58) Field of Classification Search CPC ........... GllC 13/0069; GllC 13/0002; GllC 13/0007...
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