Grapefruit–medication interactions: Forbidden fruit or avoidable consequences?

Bailey, David G.; Dresser, George K.; Arnold, J. Malcolm O.

doi:10.1503/cmaj.120951

Cited by 215 publications

(170 citation statements)

References 46 publications

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“…A well studied "perpetrator" diet-derived substance is grapefruit juice, which contains furanocoumarins that inhibit intestinal CYP3A4 via mechanism-based inhibition with subsequent protein degradation (Paine and Oberlies, 2007). More than 85 medications are vulnerable to the "grapefruit juice effect," of which the labeling for several includes cautionary statements (Bailey et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Identification of Diet-Derived Constituents as Potent Inhibitors of Intestinal Glucuronidation

et al. 2014

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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 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 IC 50 determination. The IC 50 values of 13 constituents/extracts (£10 mM with 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 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.

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Section: Introductionmentioning

confidence: 99%

Identification of Diet-Derived Constituents as Potent Inhibitors of Intestinal Glucuronidation

et al. 2014

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“…Esterases can also be involved in the hydrolysis of the metabolites of xenobiotics (Fukami & Yokoi ibid.). These concepts are not only important for the preparation of prodrugs using esters and amides (Rautio et al 2008) but also interactions between food and drugs, such as the well-known interactions between grapefruit juice and many drugs (Bailey et al 1998;Bailey et al 2013;Ogu & Maxa 2000). The reinforcement of these important concepts is the second learning outcome of this experiment.…”

Section: Research Articlementioning

confidence: 97%

Development of a versatile laboratory experiment to teach the metabolic transformation of hydrolysis

Campanile

Morral

Aljammal

et al. 2016

British Journal of Pharmacy

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In this paper we describe an easy, reliable, versatile and inexpensive laboratory experiment to teach the metabolic transformation of hydrolysis to Pharmacy students. The experiment does not require the sacrifice of any experimental animal, or any work with organs or tissues, and so can be implemented in a typical university chemistry laboratory. We used acetylsalicylic acid (ASA), hexyl salicylate (HS) and two enzymes, a lipase and an esterase. Since both ASS and HS liberate salicylic acid (SA) upon hydrolysis, students can evaluate the different enzymatic transformations by monitoring the amount of SA liberated. The learning outcomes are an enhanced student understanding of: (1) the process of hydrolysis; (2) the application of enzymatic transformations of molecules from food to xenobiotics; (3) the differences between the general specificity of substrate of both enzymes; (4) the concepts of the lipophilic pocket; (5) the catalytic triad and its regioselectivity in relation to the ester bond. A questionnaire was administered to participating students at three points in time: at the beginning of the module, after enzymatic hydrolysis was taught in class, and after the laboratory experiment. From an analysis of the questionnaire data we conclude that this practical helped Pharmacy students to understand these concepts.

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“…Mechanismbased inhibition of intestinal CYP3A4 by constituents in grapefruit juice is an extensively studied example that translates to clinically relevant interactions (Won et al, 2010(Won et al, , 2012Bailey et al, 2013). Raloxifene exhibits an extremely low oral bioavailability (,2%) due primarily to rapid presystemic glucuronidation in the intestine (Kemp et al, 2002;Dalvie et al, 2008;Cubitt et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Milk Thistle Constituents Inhibit Raloxifene Intestinal Glucuronidation: A Potential Clinically Relevant Natural Product–Drug Interaction

et al. 2015

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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 IC 50 s £ 10 mM. 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 49-and 6-glucuronidation in all enzyme systems. The K i s (human intestinal microsomes, 27-66 mM; UGT1A1, 3.2-8.3 mM; UGT1A8, 19-73 mM; and UGT1A10, 65-120 mM) encompassed reported intestinal tissue concentrations (20-310 mM), 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.

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Grapefruit–medication interactions: Forbidden fruit or avoidable consequences?

Cited by 215 publications

References 46 publications

Identification of Diet-Derived Constituents as Potent Inhibitors of Intestinal Glucuronidation

Identification of Diet-Derived Constituents as Potent Inhibitors of Intestinal Glucuronidation

Development of a versatile laboratory experiment to teach the metabolic transformation of hydrolysis

Milk Thistle Constituents Inhibit Raloxifene Intestinal Glucuronidation: A Potential Clinically Relevant Natural Product–Drug Interaction

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