Article Figures & Data
Figures
- Fig. 1.
Pathways to drug interaction testing for new chemical entities and natural products: comparison of drug interaction identification processes for new chemical entities (NCEs) (solid arrows) versus natural products (dashed arrows). Drug interaction testing for NCEs is an early step during preclinical assessment, which includes predicting pharmacokinetic drug-drug interactions using in vitro data and static or dynamic models to guide the need for clinical assessment. In contrast, drug interaction testing for natural products is not required and is typically conducted after case reports of unexpected adverse drug reactions or an unexpected loss of efficacy has been reported in humans.
- Fig. 2.
Workflow for identifying natural products as high-risk precipitants of pharmacokinetic natural product–drug interactions (NPDIs). An initial list of natural products (NPs) was gathered from HerbalGram and the University of Washington Drug Interaction Database. A series of elimination steps were used to triage 42 of these NPs, leaving five for advancement to NPDI studies by the NaPDI Center.
- Fig. 3.
The NaPDI fulcrum model: balancing evidence in natural product–drug interaction prediction. A qualitative, conceptual decision tool, termed the fulcrum model, was developed to facilitate selection of the final list of high-priority natural products for drug interaction liability testing by the NaPDI Center. The magnitude of evidence gaps in mechanistic (“M”) and descriptive (“D”) data categories were balanced against each other. Natural products for which moderate levels of evidence gaps balanced each other were prioritized over those that had too few gaps (small circles), many gaps (large circles), and/or unbalanced gaps.
Tables
- TABLE 1
Initial list of 47 candidate natural products to study as precipitants of pharmacokinetic natural product–drug interactions
Candidates 1–40 were obtained from the 2015 HerbalGram report of the top 40 herbal products by sales (Smith, 2015). Candidates without a sales rank were obtained from the University of Washington Drug Interaction Database (https://www.druginteractioninfo.org/).
Rank Natural Product Rank Natural Product 1 Horehound 25 Chia seed/chia oil 2 Cranberry 26 Turmeric 3 Echinacea 27 Maca 4 Black cohosh 28 Fenugreek 5 Flaxseed/flaxseed oil 29 Isoflavones 6 Valerian 30 Ginseng 7 Yohimbe 31 St. John’s wort 8 Bioflavonoid complex 32 Green tea 9 Saw palmetto 33 Fennel 10 Ginger 34 Horsetail 11 Aloe vera 35 Tribulus 12 Milk thistle 36 White kidney bean 13 Garlic 37 Evening primrose oil 14 Cinnamon 38 Kelp 15 Rhodiola 39 Gymnema 16 Horny goat weed 40 Grass 17 Ginkgo — Berberine 18 Plant sterols — Cannabinoids 19 Red yeast rice — Feverfew 20 Elderberry — Glycyrrhizin 21 Guarana — Goldenseal 22 Coconut oil — Shisandra chinensis 23 Senna — Resveratrol 24 Ivy leaf - TABLE 2
Precipitant natural product candidates advanced to phase II
Twenty-three products, with entries listed by descending priority level.
Natural Product Presence of In Vivo Interaction (count)a Absence of In Vivo Interaction (count)b Total In Vivo Interactions (count) Total In Vitro Targets (count)c Priority Level Cannabinoids 9 7 16 11 High Ginseng 5 3 8 5 High Green tea 5 5 10 13 High Berberine (from goldenseal) 5 3 8 12 High Resveratrol 5 0 5 25 High Garlic 4 9 13 5 High Glycyrrhizin (from licorice) 3 1 4 14 High Goldenseal 2 2 4 3 High Cinnamon 1 0 1 2 High Red yeast rice 1 1 2 1 High Turmeric 1 0 1 3 High Schisandra chinensis extract 1 0 1 1 High Ginkgo 8 32 40 21 Intermediate Echinacea 4 15 19 9 Intermediate Cranberry (juice) 2 10 12 4 Intermediate Black cohosh 1 5 6 4 Intermediate St. John’s wort 50 27 77 12 Low Milk thistle (including silymarin and silibinin) 31 17 48 54 Low Evening primrose oil 1 0 1 0 Low Echinacea (extract combination) 0 1 1 1 Low Valerian 0 6 6 7 Low Saw palmetto 0 6 6 6 Low Ginger 0 3 3 2 Low ↵a Reports indicating ≥20% change in object drug AUC.
↵b Reports indicating <20% change in object drug AUC.
↵c Reports of in vitro enzyme-, transporter-, or nuclear receptor-mediated interactions (inhibition, induction, or activation). Data were extracted from the University of Washington Drug Interaction Database (https://www.druginteractioninfo.org/) and tabulated.
Constituent(s)/Natural Product Structural Alert Alert Substructure Flavonoids, phenylpropanoids/Echinacea Glycyrrhizin, glycyrrhizinic acid/licorice Catechols 
Isoquinoline alkaloids/goldenseal Terpenoids/cinnamon Curcuminoids/turmeric Masked catechol Isoquinoline alkaloids/goldenseal Shizandrins/Schisandra spp. Gomisins/Schisandra spp. Methylene dioxyphenyl Cycloartenol/black cohosh Subterminal olefin Polyacetylenes/Echinacea Terminal and subterminal acetylenes Terpenoids/cinnamon Diallyl di- and trisulfides/garlic Terminal olefin Cinnamaldehyde/cinnamon α,β-Unsaturated aldehyde Curcuminoids/turmeric α,β-Unsaturated ketone
Data Supplement
- Supplemental Table -
Gap analysis and executive summary form
- Supplemental Table -
