OF THE PHARMACOLOGY CORE (CORE 1) The ever-increasing and often non-disclosed use of natural products (NPs) raise concerns about natural product-drug interactions (NPDIs) that, like drug-drug interactions (DDIs), may negatively impact therapeutic outcomes. As with DDIs, the most common mechanisms underlying NPDIs include induction and inhibition of drug metabolizing enzymes or transporters. Given the chemistry complexity of the many phytoconstituents, the major issue with NPs is in identifying and isolating the perpetrating constituent(s) for mechanistic studies in vitro and elucidating its (their) pharmacokinetics as an in vivo determinant of clinically relevant NPDIs in human subjects. Hence, evaluating the drug interaction liability of a given NP requires a rigorous ?predict, learn, and confirm? approach involving robust human-derived in vitro systems, dynamic modeling and simulation, and clinical assessment. Dr. Paine, Co-PI and Pharmacology Core leader, has extensive investigative experience in pharmacokinetic NPDIs using the aforementioned approach, and her UW Co-Investigators are international leaders in the field of DDIs, who have developed state-the-the-art in vitro methods for studying DDIs mediated by biotransformation enzymes and/or transport proteins. Their collective expertise will enable the Pharmacology Core to develop a comprehensive and systematic approach for solving the scientific and technical challenges in assessing the interaction potential and clinical relevance of NPDIs. The Pharmacology Core is responsible for 1) selecting and prioritizing 4-6 natural products (NPs) for further investigation in the Interaction Projects, and 2) developing detailed Statements of Work (SOWs) for the Interaction Projects. The Pharmacology Core has developed an innovative NP selection strategy, which combines mechanistic and practical considerations, along with input from the Analytical and Informatics Cores, that will enable accomplishment of the first objective. As an illustration of this approach, a list of five priority NPs were identified: cannabinoids (marijuana), green tea, St. John?s wort, 6?,7?-dihydroxybergottamin (DHB) supplements, and milk thistle. The second objective will be accomplished by entering the approved NPs into an assessment process guided by a three-part Decision Tree as outlined in the Research Strategy of the Overall section. Some of the novel methods introduced into the Decision Trees include the newer human- derived cell systems (e.g., cell lines expressing recombinant transporters), ?Phase 0? pharmacokinetic studies with a candidate NP in healthy subjects, and use of physiologically-based pharmacokinetic modeling. Based on the systematic assessment, the Pharmacology Core will develop SOWs for the in vitro and in vivo studies of the Interaction Projects. Thereafter, the Pharmacology Core will participate in the interaction Project Teams to oversee the execution of the in vitro and clinical studies detailed in the SOWs, analyze the pharmacokinetic data generated by the Analytical Core, and help in coordinating data transfer to the Informatics Core. Well- designed and carefully executed NPDI studies will provide new standards for NPDI research.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AT008909-02
Application #
9135205
Study Section
Special Emphasis Panel (ZAT1-PK)
Program Officer
Hopp, Craig
Project Start
Project End
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
2
Fiscal Year
2016
Total Cost
$277,140
Indirect Cost
$45,655
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Paine, Mary F; Shen, Danny D; McCune, Jeannine S (2018) Recommended Approaches for Pharmacokinetic Natural Product-Drug Interaction Research: a NaPDI Center Commentary. Drug Metab Dispos 46:1041-1045
Caesar, Lindsay K; Kvalheim, Olav M; Cech, Nadja B (2018) Hierarchical cluster analysis of technical replicates to identify interferents in untargeted mass spectrometry metabolomics. Anal Chim Acta 1021:69-77
Johnson, Emily J; González-Peréz, Vanessa; Tian, Dan-Dan et al. (2018) Selection of Priority Natural Products for Evaluation as Potential Precipitants of Natural Product-Drug Interactions: A NaPDI Center Recommended Approach. Drug Metab Dispos 46:1046-1052
Tian, Dan-Dan; Kellogg, Joshua J; Okut, Ne?e et al. (2018) Identification of Intestinal UDP-Glucuronosyltransferase Inhibitors in Green Tea (Camellia sinensis) Using a Biochemometric Approach: Application to Raloxifene as a Test Drug via In Vitro to In Vivo Extrapolation. Drug Metab Dispos 46:552-560
Judkins, John; Tay-Sontheimer, Jessica; Boyce, Richard D et al. (2018) Extending the DIDEO ontology to include entities from the natural product drug interaction domain of discourse. J Biomed Semantics 9:15
Kellogg, Joshua J; Graf, Tyler N; Paine, Mary F et al. (2017) Comparison of Metabolomics Approaches for Evaluating the Variability of Complex Botanical Preparations: Green Tea (Camellia sinensis) as a Case Study. J Nat Prod 80:1457-1466
Kellogg, Joshua J; Wallace, Emily D; Graf, Tyler N et al. (2017) Conventional and accelerated-solvent extractions of green tea (camellia sinensis) for metabolomics-based chemometrics. J Pharm Biomed Anal 145:604-610