Isolation and Identification of Intestinal CYP3A Inhibitors from Cranberry (<i>Vaccinium macrocarpon</i>) Using Human Intestinal Microsomes

Kim, Eunkyung; Sy-Cordero, Arlene A.; Graf, Tyler N.; Brantley, Scott J.; Paine, Mary F.; Oberlies, Nicholas H.

doi:10.1055/s-0030-1250259

Cited by 38 publications

(36 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This framework centers on the evaluation of isolated constituents to ascertain the relative contribution of each constituent to the mixture, as well as to identify marker constituents that can be used to predict the likelihood and magnitude of these interactions. As an extension of previous studies focused on cytochrome P450-mediated inhibition (Brantley et al, 2010(Brantley et al, , 2013(Brantley et al, , 2014bKim et al, 2011), this framework was applied to 13 isolated constituents and 2 extracts as inhibitors of glucuronidation with a focus on gut-relevant enzymes.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Some herbal products, including St. John's wort and milk thistle, are well characterized, and individual constituents have been isolated in quantities sufficient for interaction screening (Obach, 2000;Weber et al, 2004;Lee et al, 2006;Graf et al, 2007;Tatsis et al, 2007;Brantley et al, 2010Brantley et al, , 2013. Other techniques, such as bioactivityguided fractionation (Kim et al, 2011a;Roth et al, 2011), can be used to elucidate the causative constituents from herbal products.…”

Section: Challenges With Evaluating and Predicting Pk Hdismentioning

confidence: 99%

Herb–Drug Interactions: Challenges and Opportunities for Improved Predictions

et al. 2013

View full text Add to dashboard Cite

Supported by a usage history that predates written records and the perception that "natural" ensures safety, herbal products have increasingly been incorporated into Western health care. Consumers often self-administer these products concomitantly with conventional medications without informing their health care provider(s). Such herb-drug combinations can produce untoward effects when the herbal product perturbs the activity of drug metabolizing enzymes and/or transporters. Despite increasing recognition of these types of herb-drug interactions, a standard system for interaction prediction and evaluation is nonexistent. Consequently, the mechanisms underlying herb-drug interactions remain an understudied area of pharmacotherapy. Evaluation of herbal product interaction liability is challenging due to variability in herbal product composition, uncertainty of the causative constituents, and often scant knowledge of causative constituent pharmacokinetics. These limitations are confounded further by the varying perspectives concerning herbal product regulation. Systematic evaluation of herbal product drug interaction liability, as is routine for new drugs under development, necessitates identifying individual constituents from herbal products and characterizing the interaction potential of such constituents. Integration of this information into in silico models that estimate the pharmacokinetics of individual constituents should facilitate prospective identification of herb-drug interactions. These concepts are highlighted with the exemplar herbal products milk thistle and resveratrol. Implementation of this methodology should help provide definitive information to both consumers and clinicians about the risk of adding herbal products to conventional pharmacotherapeutic regimens.

show abstract

“…Such experiments provide mechanistic information about inhibitory capacities, as well as specific enzymes and/or transporters involved. Two examples illustrating the aforementioned approach as it applies to drug metabolism and transport are discussed (Kim et al, 2011; Roth et al, 2011). …”

Section: Challenges In Establishing Clinical Significancementioning

confidence: 99%

“…A series of bioactivity-guided fractionation studies with whole cranberry ( Vaccinium macrocarpon Ait.) were initiated next to identify potential specific enteric CYP3A inhibitors in cranberry (Kim et al, 2011). Using human intestinal microsomes and recombinant CYP3A4, three triterpenes (maslinic acid, corosolic acid, ursolic acid) were isolated.…”

Section: Challenges In Establishing Clinical Significancementioning

confidence: 99%

Mechanisms underlying food–drug interactions: Inhibition of intestinal metabolism and transport

Won

Oberlies

Paine

2012

Pharmacology & Therapeutics

118

View full text Add to dashboard Cite

Food-drug interaction studies are critical to evaluate appropriate dosing, timing, and formulation of new drug candidates. These interactions often reflect prandial-associated changes in the extent and/or rate of systemic drug exposure. Physiologic and physicochemical mechanisms underlying food effects on drug disposition are well-characterized. However, biochemical mechanisms involving drug metabolizing enzymes and transport proteins remain underexplored. Several plant-derived beverages have been shown to modulate enzymes and transporters in the intestine, leading to altered pharmacokinetic (PK) and potentially negative pharmacodynamic (PD) outcomes. Commonly consumed fruit juices, teas, and alcoholic drinks contain phytochemicals that inhibit intestinal cytochrome P450 and phase II conjugation enzymes, as well as uptake and efflux transport proteins. Whereas myriad phytochemicals have been shown to inhibit these processes in vitro, translation to the clinic has been deemed insignificant or undetermined. An overlooked prerequisite for elucidating food effects on drug PK is thorough knowledge of causative bioactive ingredients. Substantial variability in bioactive ingredient composition and activity of a given dietary substance poses a challenge in conducting robust food-drug interaction studies. This confounding factor can be addressed by identifying and characterizing specific components, which could be used as marker compounds to improve clinical trial design and quantitatively predict food effects. Interpretation and integration of data from in vitro, in vivo, and in silico studies require collaborative expertise from multiple disciplines, from botany to clinical pharmacology (i.e., plant to patient). Development of more systematic methods and guidelines is needed to address the general lack of information on examining drug-dietary substance interactions prospectively.

show abstract

Isolation and Identification of Intestinal CYP3A Inhibitors from Cranberry (Vaccinium macrocarpon) Using Human Intestinal Microsomes

Cited by 38 publications

References 27 publications

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

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

Herb–Drug Interactions: Challenges and Opportunities for Improved Predictions

Mechanisms underlying food–drug interactions: Inhibition of intestinal metabolism and transport

Contact Info

Product

Resources

About