Interpatient variability in drug response is an ongoing complication in clinical practice that can delay, or even prevent, optimal therapeutic outcome, with consequent negative impact on quality of life and health care costs. Variable drug response is due in part to interindividual differences in processing xenobiotics via absorption, distribution, and elimination. While substantial resources have been invested in delineating genetic factors associated with variable drug disposition, comparatively less attention has been given to non-genetic factors, which are at least as important determinants of drug response. Intentional ingestion of dietary substances, as foods or supplements, likely constitutes the largest portion of environmental exposure to chemicals. Because dietary substances are not regulated in the same manner as drugs, evaluation of drug interaction liability for these substances is not required prior to marketing;compared to drug-drug interactions, drug-diet interactions remain understudied, underreported, and misunderstood. This knowledge deficit is compounded by a lack of translational research methodologies aimed at prospective evaluation of these interactions, which are especially challenging to assess because, unlike most drug products, dietary substances are mixtures, composed of multiple, and often unknown, bioactive ingredients. Partnering between clinical pharmacologists and natural products chemists is a logical strategy for identifying and characterizing drug-diet interactions in a time- and cost-efficient manner. Such a partnership is the foundation of the present application, which uses the model dietary substances silymarin, an extract of the top ten-selling supplement milk thistle, and grapefruit juice (GFJ) to test the central hypothesis that an interactive in vitro-in silico-in vivo approach can elucidate specific bioactive ingredients and mechanisms underlying drug-diet interactions. Preliminary data indicate that constituents in these mixtures are potent inhibitors of intestinal cytochrome P450 3A (CYP3A)-mediated metabolism (silymarin) or organic anion transporting polypeptide (OATP)-mediated absorptive uptake (GFJ), two important processes at the primary portal of drug and dietary substance entry into the body. The proposed studies compose a framework for developing rigorous guidelines for prospective evaluation of drug-diet interactions. Human-derived in vitro systems will be used to identify individual bioactive constituents and to recover robust parameters associated with absorptive permeability and enteric CYP3A or OATP inhibition by single constituents and the natural mixture. The in vitro parameters recovered will be used to develop in silico models to predict the magnitude of effect of the dietary substance on systemic exposure to a model drug, informing clinical study design. Finally, accuracy of the in silico models will be evaluated in proof-of-concept clinical studies. The information gained in this effort will further leverage existing knowledge of genetic and non-genetic factors that determine drug response, and will progress towards the long-term goal of providing firm information to clinicians for managing drug-diet interactions appropriately.
People frequently take their medicines with food, and approximately 20% of adults take their medicines with dietary supplements;consequently, the chances of an adverse interaction between a drug and constituents in these dietary substances are very high. This grant proposal will investigate how model dietary substances milk thistle and grapefruit juice interfere with the body's ability to process drugs. The knowledge gained will assist health care providers in making informed decisions about managing potential drug-dietary substance interactions appropriately.
|Johnson, Emily J; Won, Christina S; Köck, Kathleen et al. (2017) Prioritizing pharmacokinetic drug interaction precipitants in natural products: application to OATP inhibitors in grapefruit juice. Biopharm Drug Dispos 38:251-259|
|Gufford, B T; Ainslie, G R; White Jr, J R et al. (2017) Comparison of a New Intranasal Naloxone Formulation to Intramuscular Naloxone: Results from Hypothesis-generating Small Clinical Studies. Clin Transl Sci 10:380-386|
|Gufford, B T; Barr, J T; González-Pérez, V et al. (2015) Quantitative prediction and clinical evaluation of an unexplored herb-drug interaction mechanism in healthy volunteers. CPT Pharmacometrics Syst Pharmacol 4:701-10|
|Barr, John T; Jones, Jeffrey P; Oberlies, Nicholas H et al. (2015) Inhibition of human aldehyde oxidase activity by diet-derived constituents: structural influence, enzyme-ligand interactions, and clinical relevance. Drug Metab Dispos 43:34-41|
|Gufford, Brandon T; Chen, Gang; Vergara, Ana G et al. (2015) Milk Thistle Constituents Inhibit Raloxifene Intestinal Glucuronidation: A Potential Clinically Relevant Natural Product-Drug Interaction. Drug Metab Dispos 43:1353-9|
|Gufford, Brandon T; Graf, Tyler N; Paguigan, Noemi D et al. (2015) Chemoenzymatic Synthesis, Characterization, and Scale-Up of Milk Thistle Flavonolignan Glucuronides. Drug Metab Dispos 43:1734-43|
|Gufford, Brandon T; Chen, Gang; Lazarus, Philip et al. (2014) Identification of diet-derived constituents as potent inhibitors of intestinal glucuronidation. Drug Metab Dispos 42:1675-83|
|Brantley, Scott J; Argikar, Aneesh A; Lin, Yvonne S et al. (2014) Herb-drug interactions: challenges and opportunities for improved predictions. Drug Metab Dispos 42:301-17|
|VanderMolen, Karen M; Ainslie, Garrett R; Paine, Mary F et al. (2014) Labeled content of two furanocoumarins in dietary supplements correlates with neither actual content nor CYP3A inhibitory activity. J Pharm Biomed Anal 98:260-5|
|Ainslie, Garrett R; Wolf, Kristina K; Li, Yingxin et al. (2014) Assessment of a candidate marker constituent predictive of a dietary substance-drug interaction: case study with grapefruit juice and CYP3A4 drug substrates. J Pharmacol Exp Ther 351:576-84|
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