Drug Interactions Within Food and Medicinal Plant Groups


Benton Bramwell, ND, and Matt Warnock, JD

We have rightly emphasized elsewhere the need to look at human data as the most definitive and informative evidence for herbal-drug interactions.  However, it is also helpful to identify categories of foods and medicinal plants with shared phytochemistry that may lead to patterns of herbal-drug interactions.  Rather than such associations being approached as definitive contraindications, knowledge of these connections may increase awareness in clinicians for the purpose of monitoring treatment pharmacokinetics and pharmacodynamics. 

Here we review the following phytochemicals that may cause drug interactions and are found in groups of foods/herbs: berberine found in barberry and various other herbs; glycoalkaloids from foods in the Solanaceae family; naringin and hesperidin as flavonoids found in citrus; furanocoumarins also found in citrus and medicinal herbs; and sulforaphane and dietary indoles derived from Brassicaceae plants.

Berberine-Containing Herbs

As an isolated and purified ingredient, berberine is now sold as a dietary ingredient in the United States.  In purified form, this chemical is known to inhibit multiple drug-metabolizing CYP enzymes, including CYP2D6, CYP2C9, and CYP3A4.1

Berberine is known to occur in many Barberry (Berberis) plants, with the fruit of some of these being edible and consumed, for example, in Iran.2 In addition to its occurrence in Berberis species,3,4 berberine is a recurring attraction also in the Mahonia genus,5 including Mahonia aquifolium, Oregon grape.6 In addition, berberine is a constituent of several herbs that may be well known to many practitioners, goldenseal root,7 the rhizome of Coptis chinensis (Chinese Goldthread),8 as well as several medicinal herbs that may be lesser known, including Thalictrum foliolosum (Leafy Meadow-Rue)9 and Coscinium fenestratum (yellow vine).10

Glycoalkaloids from Solanaceae

The nightshade plants from the family Solanaceae (potatoes, tomatoes, eggplant and peppers), are a dietary source of glycoalkaloids, including solanine and chaconine as the major alkaloids present in potato,11,12 hydroxytomatine/tomatine  as the major alkaloids in tomato,13 and solmargine/solasonine from eggplant.14 The presence of glycoalkaloids in green and red peppers (Capsicum annuum) has also been reported,15 though information as to which specific species of glycoalkaloids are present and predominant is more scarce at present. While solanine has not been shown to have much effect on the drug-metabolizing enzymes of the CYP450 system,16 there are potential interactions between Solanaceae alkaloids and cholinesterase inhibitors that may prove to be clinically relevant.  In an in vitro testing system, a concentration of about 34 ppm of chaconine and solanine led to roughly a 25% inhibition of cholinesterase; inhibition by tomatine was also seen, though at a lower level of about 4%.17

Cholinesterase inhibition is also shown in vitro with eggplant, and more especially aqueous extracts of the peel and pulp.18 In vitro work shows that the cholinesterase inhibiting effects of solanine and chaconine are more pronounced on butyrylcholinesterase (BuChE) than acetylcholinesterase;  moreover, these inhibitory effects on the former occur with alkaloid concentrations in the nanomolar range,19 a level that overlaps serum levels obtained after humans eat a serving of mashed potatoes.20,21 Further data from McGehee (2019) show that the cholinesterase inhibitory effects of chaconine and solanine are additive to cholinesterase-inhibiting drugs.  Additionally, their administration has been shown to lead to increased levels of Mivacurium (which undergoes metabolism by BuChE) and prolonged Mivacurium-induced paralysis in rabbits.  Given half-lives for solanine and chaconine of 11 and 19 hours (Hellenas 1992) and some cholinesterase inhibition reported across members of the Solanaceae family, it seems wise to at least be aware of the pattern of consumption of Solanaceae foods prior to the administration of medications affected by cholinesterase.

Flavonoid and Furanocoumarin Drug Interactions

Elsewhere we have reviewed interactions associated with the catechins (flavanols within the flavonoid family) of green tea, specifically observed reductions in the concentrations of rosuvastatin,22 atorvastatin,23 lisinopril,24 nadolol,25 and nintedanib26 when green tea or its catechins are administered concomitantly with these medications.

Another flavonoid, naringin, found in grapefruit (like other citrus a member of the Rutaceae family), was previously proposed to account for inhibition of CYP enzyme activity and known grapefruit juice-drug interactions,27 particularly increases in felodipine concentrations, a change in pharmacokinetics that is known to be a sensitive marker of strong CYP3A4 inhibition.28 However, while it is true that naringin may act as a competitive inhibitor of CYP3A4 (and relatively high concentrations of naringin exist in fruit segments vs juice), it now seems that several furanocoumarin species (Bergamottin, 6’-7-dihydroxybergamottin) are the potent “mechanism-based” irreversible  inhibitors of CYP3A4 inhibitors in grapefruit juice.29 Indeed, grapefruit juice free of these  furanocoumarins but containing the flavonoids has not been shown to affect felodipine pharmacokinetics that are mediated by intestinal CYP3A4.30 Nor for that matter has isolated naringin delivered in water at a concentration equivalent to that of juice shown any significant effect on felodipine pharmacokinetics compared to water itself.31

An additional aspect of drug absorption affected by flavonoids is intestinal absorption of drugs impacted by membrane transporters known as the organic anion transporting polypeptides (OATP).  Members of this polypeptide family play a critical role in the uptake of fexofenadine,32 an antihistamine, as well as some other drugs.33

Naringin and hesperidin (hesperidin being found in oranges) each show inhibition of some members of the OATP family in vitro, which would reduce intestinal uptake of drugs transported through this system.  Moreover, grapefruit, orange and apple juices all are shown to significantly reduce the plasma area under the concentration-time curve of fexofenadine in humans subjects.34 Specifically with regard to the uptake of fexofenadine, it appears that the 1A2 polypeptide in the OATP family regulates fexofenadine uptake, with naringin from grapefruit inhibiting OAPT1A2 uptake in humans and hesperidin from orange juice considered likely to mediate the same effect, based on in vitro testing.35

While furanocoumarins do not seem to impact the uptake of fexofenadine mediated specifically by OATP1A2 (Bailey 2007), there are other members of this polypeptide family inhibited by furanocoumarins in vitro, including potent inhibition of rat OATP3 and OATP1 by 6’-7’-Dihydroxybergamottin (Dresser 2002). 

Thus, there may be situations where the observed pharmacokinetics of a given drug manifest based on a complex interplay between flavonoids and furanocoumarins affecting both multiple drug transporters and CYP family enzymes (Dresser 2002).

Before leaving the aforementioned furanocoumarins present in grapefruit, it is also important to note that these important CYP3A4 inhibitors occur not only in grapefruit, but also in related fruits including pomelos (and indeed pomelos has been shown to alter cyclosporine levels in humans36), citrons, and papedas; however, mandarins have virtually no furanocoumarins.37 Furanocoumarins (bergamottin, 5-methoxypsoralen) have also been reported in bergamot.38 Thus, where concerns about grapefruit juice and drug interactions exist, the related citrus of concern above should also be avoided, while mandarins may provide a welcome alternative. 

Additionally, quite recent work shows aqueous extracts of some plants from both the Apiaceae and Rutaceae families, most notably Ammi majus (Queen Anne’s Lace), Angelica archangelica (Norwegian angelica), Cnidium monnieri (Monnier’s snowparsley), and Ruta graveolens (Garden rue), are of concern for inhibiting CYP1A2 enzyme function due to furanocoumarin content.  Hot water extracts made from gram quantities of these herbs (4.5 g and 9.0 grams used to make A. archangelica root extracts studied; 6.0 g and 12.0 g used to make A. majus seed extracts studied; and 3.0 g used to make C. monnieri fruit and R. graveolens leaf extracts studied). 

The furanocoumarins reportedly identified in these extracts (8-methoxypsoralen, 5-methoxypsoralen, and isopsoralen) suggest a slightly different furanocoumarin profile than that reported for grapefruit (Bergamottin and 6’-7-dihydroxybergamottin), though the extracts share the presence of one of the furanocoumarins to date found in bergamot (5-methoxypsoralen). Consumption of the herbal extracts led to quite large differences in caffeine AUC observed in human subjects, with increases ranging between 1.3- and 4.3-fold.39 These large increases in AUC were accompanied by significantly slower clearance of caffeine. 

Moreover, the authors of this study point to irreversible inhibition of CYP1A2 by the furanocoumarins present (indicated by inhibition being dependent on pre-incubation time and concentration) and highlight the possibility that binding of the furanocoumarins present in these extracts may lead to destruction of CYP1A2, thus delaying caffeine metabolism until new enzyme can be synthesized by the body. 

In a highly caffeinated world, it seems especially important to make sure patients know to avoid caffeine when taking extracts from the species above.  Interestingly, however, grapefruit has not been shown to alter caffeine pharmacokinetics,40 implying that the difference in furanocoumarin profile between grapefruit and the herbal extracts above leads to functional differences. Whether bergamot might affect caffeine metabolism appears to be unknown at present.

Sulforaphane and Dietary Indoles

Plants from the Brassicaceae family (including cabbage, brussels sprouts, broccoli, cauliflower, radish, turnip, swede, rocket salad, mustard, and wasabi) are the major dietary sources of glucosinolates (sulfur-containing glycosides) in the diet.41 The glucosinolates in many of these vegetables are hydrolyzed by the enzyme myrosinase (activated with plant tissue is torn), liberating isothiocyanate compounds, including sulforaphane, which is derived from the glucosinolate glucoraphanin.  In several of its most commonly consumed food sources, sulforaphane is derived in greater quantity from  broccoli, followed by purple cabbage, followed by green cabbage.42

The indole glucosinolate, glucobrassicin, ends up being broken down most often into indole-3-carbinol, which can be polymerized into its dimer, 3,3’-diindolylmethane.43 Both sulforaphane and indole-3-carbinol (and its polymers collectively referred to here as dietary indoles) may have important effects on drug metabolism, which are briefly discussed below.

Based on in vitro work in Caco-2 cells,44 there is the potential for sulforaphane to affect rate of drug metabolism based on changes in the expression of phase II enzymes such as NADPH: quinine reductase and isoenzymes of glutathione transferase, as well as expression of the gene encoding the cellular drug transporter, multidrug resistance protein.  The in vitro data thus far suggests that interactions between sulforaphane and drugs (furosemide, verapamil, and ketoprofen were used in the cited study by Lubelska) are very dependent upon concentration and timing of cellular exposure to both sulforaphane and any given drug.  Thus, it will probably be the case that only in vivo human studies will be able to clarify interactions that exist under usual conditions of use, and thus human studies exploring sulforaphane-drug interactions are needed.  

It is interesting that sulforaphane and apigenin, a flavonoid found in sources such as parsley, celery, chamomile, artichokes, and oregano45 appear to exert an up to 12-fold increase in the expression of mRNA for the phase II enzyme UDP-glucuronosyltransferase (1A1), again in a caco-2 model.46

Dietary indoles are unique in that they both induce the activity of CYP enzymes (especially CYP1A1), but also inhibit the catalytic activity of the flavin-containing monooxygenase 1 protein, which is also active in drug metabolism.  In vitro work using a rat liver microsome model suggests the potential for altered toxicity for drugs, such as tamoxifen and nicotine, that undergo metabolism via both enzyme pathways.47 Also, dietary indoles have demonstrated inhibitory activity on the drug efflux transporter p-glycoprotein, both in vitro and in mice.  Here again, work in humans is needed to understand the composite effects of dietary indoles on drug metabolism.

Like other areas of drug interaction data, human data can best clarify which interactions are of clinical concern; but thinking in terms of shared chemistry present in foods and herbs may increase clinical awareness and appropriate monitoring.

References

  1. Guo Y, Chen Y, Tan ZR, Klaassen CD, Zhou HH. Repeated administration of berberine inhibits cytochromes P450 in humans. Eur J Clin Pharmacol. 2012 Feb;68(2):213-7. doi: 10.1007/s00228-011-1108-2. Epub 2011 Aug 26. PMID: 21870106; PMCID: PMC4898966.
  2. Sarraf M, Beig Babaei A, Naji-Tabasi S. Investigating functional properties of barberry species: an overview. J Sci Food Agric. 2019 Sep;99(12):5255-5269. doi: 10.1002/jsfa.9804. Epub 2019 Jun 27. PMID: 31077383.
  3. Katare AK, Singh B, Shukla P, Gupta S, Singh B, Yalamanchili K, Kulshrestha N, Bhanwaria R, Sharma AK, Sharma S, Sneha, Mindala DP, Roy S, Kalgotra R. Rapid determination and optimisation of berberine from Himalayan Berberis lycium by soxhlet apparatus using CCD-RSM and its quality control as a potential candidate for COVID-19. Nat Prod Res. 2022 Feb;36(3):868-873. doi: 10.1080/14786419.2020.1806274. Epub 2020 Aug 13. PMID: 32787584.
  4. Roy NS, Choi IY, Um T, Jeon MJ, Kim BY, Kim YD, Yu JK, Kim S, Kim NS. Gene Expression and Isoform Identification of PacBio Full-Length cDNA Sequences for Berberine Biosynthesis in Berberis koreana. Plants (Basel). 2021 Jun 28;10(7):1314. doi: 10.3390/plants10071314. PMID: 34203474; PMCID: PMC8308982.
  5. Ji X, Li Y, Liu H, Yan Y, Li J. Determination of the alkaloid content in different parts of some Mahonia plants by HPCE. Pharm Acta Helv. 2000 Apr;74(4):387-91. doi: 10.1016/s0031-6865(99)00061-8. PMID: 10812938.
  6. Galle K, Müller-Jakic B, Proebstle A, Jurcic K, Bladt S, Wagner H. Analytical and pharmacological studies on Mahonia aquifolium. Phytomedicine. 1994 Jun;1(1):59-62. doi: 10.1016/S0944-7113(11)80024-3. PMID: 23195817.
  7. Weber HA, Zart MK, Hodges AE, White KD, Barnes SM, Moody LA, Clark AP, Harris RK, Overstreet JD, Smith CS. Method validation for determination of alkaloid content in goldenseal root powder. J AOAC Int. 2003 May-Jun;86(3):476-83. PMID: 12852562.
  8. He F, Huang YF, Dai W, Qu XY, Lu JG, Lao CC, Luo WH, Sun DM, Wei M, Xiao SY, Xie Y, Liu L, Zhou H. The localization of the alkaloids in Coptis chinensis rhizome by time-of-flight secondary ion mass spectrometry. Front Plant Sci. 2022 Dec 23;13:1092643. doi: 10.3389/fpls.2022.1092643. PMID: 36618650; PMCID: PMC9816869.
  9. Pandey G, Khatoon S, Pandey MM, Rawat AKS. Altitudinal variation of berberine, total phenolics and flavonoid content in Thalictrum foliolosum and their correlation with antimicrobial and antioxidant activities. J Ayurveda Integr Med. 2018 Jul-Sep;9(3):169-176. doi: 10.1016/j.jaim.2017.02.010. PMID: 29102462; PMCID: PMC6148047.
  10. Rojsanga P, Gritsanapan W, Suntornsuk L. Determination of berberine content in the stem extracts of Coscinium fenestratum by TLC densitometry. Med Princ Pract. 2006;15(5):373-8. doi: 10.1159/000094272. PMID: 16888396.
  11. Houben RJ, Brunt K.  Determination of glycoalkaloids in potato tubers by reversed-phase high performance liquid chromatography. Journal of Chromatography A 1994; 661(1-2):169-174.
  12. Roddick JG, Melchers G. Steroidal glycoalkaloid content of potato, tomato and their somatic hybrids. Theor Appl Genet. 1985 Sep;70(6):655-60. doi: 10.1007/BF00252292. PMID: 24253124.
  13. Dzakovich MP, Hartman JL, Cooperstone JL. A High-Throughput Extraction and Analysis Method for Steroidal Glycoalkaloids in Tomato. Front Plant Sci. 2020;11:767. Published 2020 Jun 18. doi:10.3389/fpls.2020.00767
  14. Mennella G, Lo Scalzo R, Fibiani M, D’Alessandro A, Francese G, Toppino L, Acciarri N, de Almeida AE, Rotino GL. Chemical and bioactive quality traits during fruit ripening in eggplant (S. melongena L.) and allied species. J Agric Food Chem. 2012 Nov 28;60(47):11821-31. doi: 10.1021/jf3037424. Epub 2012 Nov 19. PMID: 23134376.
  15. Jones PG, Fenwick GR. The glycoalkaloid content of some edible solanaceous fruits and potato products. J Sci Food Agric. 1981 Apr;32(4):419-21. doi: 10.1002/jsfa.2740320418. PMID: 7242021.
  16. Peeples A, Dalvi RR. Toxic alkaloids and their interaction with microsomal cytochrome P-450 in vitro. J Appl Toxicol. 1982 Dec;2(6):300-2. doi: 10.1002/jat.2550020607. PMID: 7185909.
  17. Bushway, R.J., Savage, S.A. & Ferguson, B.S. Inhibition of acetyl cholinesterase by solanaceous glycoalkaloids and alkaloids. American Potato Journal 64, 409–413 (1987). https://doi.org/10.1007/BF02853703.
  18. Lelario F, De Maria S, Rivelli AR, Russo D, Milella L, Bufo SA, Scrano L. A Complete Survey of Glycoalkaloids Using LC-FTICR-MS and IRMPD in a Commercial Variety and a Local Landrace of Eggplant (Solanum melongena L.) and their Anticholinesterase and Antioxidant Activities. Toxins (Basel). 2019 Apr 19;11(4):230. doi: 10.3390/toxins11040230. PMID: 31010145; PMCID: PMC6521288.
  19. McGehee DS, Krasowski MD, Fung DL, Wilson B, Gronert GA, Moss J. Cholinesterase inhibition by potato glycoalkaloids slows mivacurium metabolism. Anesthesiology. 2000 Aug;93(2):510-9. doi: 10.1097/00000542-200008000-00031. PMID: 10910502.
  20. Harvey MH, McMillan M, Morgan MR, Chan HW. Solanidine is present in sera of healthy individuals and in amounts dependent on their dietary potato consumption. Hum Toxicol. 1985 Mar;4(2):187-94. doi: 10.1177/096032718500400209. PMID: 4007882.
  21. Hellenäs KE, Nyman A, Slanina P, Lööf L, Gabrielsson J. Determination of potato glycoalkaloids and their aglycone in blood serum by high-performance liquid chromatography. Application to pharmacokinetic studies in humans. J Chromatogr. 1992 Jan 3;573(1):69-78. doi: 10.1016/0378-4347(92)80476-7. PMID: 1564109.
  22. Kim TE, Ha N, Kim Y, Kim H, Lee JW, Jeon JY, Kim MG. Effect of epigallocatechin-3-gallate, major ingredient of green tea, on the pharmacokinetics of rosuvastatin in healthy volunteers. Drug Des Devel Ther. 2017 May 9;11:1409-1416. doi: 10.2147/DDDT.S130050. PMID: 28533679; PMCID: PMC5431696.
  23. Abdelkawy KS, Abdelaziz RM, Abdelmageed AM, Donia AM, El-Khodary NM. Effects of Green Tea Extract on Atorvastatin Pharmacokinetics in Healthy Volunteers. Eur J Drug Metab Pharmacokinet. 2020 Jun;45(3):351-360. doi: 10.1007/s13318-020-00608-6. PMID: 31997084.
  24. Misaka S, Ono Y, Uchida A, Ono T, Abe O, Ogata H, Sato H, Suzuki M, Onoue S, Shikama Y, Shimomura K. Impact of Green Tea Catechin Ingestion on the Pharmacokinetics of Lisinopril in Healthy Volunteers. Clin Transl Sci. 2021 Mar;14(2):476-480. doi: 10.1111/cts.12905. Epub 2020 Oct 22. PMID: 33048477; PMCID: PMC7993260.
  25. Misaka S, Abe O, Ono T, Ono Y, Ogata H, Miura I, Shikama Y, Fromm MF, Yabe H, Shimomura K. Effects of single green tea ingestion on pharmacokinetics of nadolol in healthy volunteers. Br J Clin Pharmacol. 2020 Nov;86(11):2314-2318. doi: 10.1111/bcp.14315. Epub 2020 May 12. PMID: 32320490; PMCID: PMC7576630
  26. Veerman GDM, van der Werff SC, Koolen SLW, Miedema JR, Oomen-de Hoop E, van der Mark SC, Chandoesing PP, de Bruijn P, Wijsenbeek MS, Mathijssen RHJ. The influence of green tea extract on nintedanib’s bioavailability in patients with pulmonary fibrosis. Biomed Pharmacother. 2022 Jul;151:113101. doi: 10.1016/j.biopha.2022.113101. Epub 2022 May 17. PMID: 35594703.
  27. Fuhr U, Kummert AL. The fate of naringin in humans: a key to grapefruit juice-drug interactions? Clin Pharmacol Ther. 1995 Oct;58(4):365-73. doi: 10.1016/0009-9236(95)90048-9. PMID: 7586927.
  28. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers Accessed 16 March 2023.
  29. Bailey DG, Dresser GK, Kreeft JH, Munoz C, Freeman DJ, Bend JR. Grapefruit-felodipine interaction: effect of unprocessed fruit and probable active ingredients. Clin Pharmacol Ther. 2000 Nov;68(5):468-77. doi: 10.1067/mcp.2000.110774. PMID: 11103749.
  30. Paine MF, Widmer WW, Hart HL, Pusek SN, Beavers KL, Criss AB, Brown SS, Thomas BF, Watkins PB. A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction. Am J Clin Nutr. 2006 May;83(5):1097-105. doi: 10.1093/ajcn/83.5.1097. Erratum in: Am J Clin Nutr. 2006 Jul;84(1):264. PMID: 16685052.
  31. Bailey DG, Arnold JM, Munoz C, Spence JD. Grapefruit juice–felodipine interaction: mechanism, predictability, and effect of naringin. Clin Pharmacol Ther. 1993 Jun;53(6):637-42. doi: 10.1038/clpt.1993.84. PMID: 8513655.
  32. Cvetkovic M, Leake B, Fromm MF, Wilkinson GR, Kim RB. OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos. 1999 Aug;27(8):866-71. PMID: 10421612.
  33. Franke RM, Scherkenbach LA, Sparreboom A. Pharmacogenetics of the organic anion transporting polypeptide 1A2. Pharmacogenomics. 2009;10(3):339-344. doi:10.2217/14622416.10.3.339
  34. Dresser GK, Bailey DG, Leake BF, Schwarz UI, Dawson PA, Freeman DJ, Kim RB. Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther. 2002 Jan;71(1):11-20. doi: 10.1067/mcp.2002.121152. PMID: 11823753.
  35. Bailey DG, Dresser GK, Leake BF, Kim RB. Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice. Clin Pharmacol Ther. 2007 Apr;81(4):495-502. doi: 10.1038/sj.clpt.6100104. Epub 2007 Feb 14. PMID: 17301733.
  36. Grenier J, Fradette C, Morelli G, Merritt GJ, Vranderick M, Ducharme MP. Pomelo juice, but not cranberry juice, affects the pharmacokinetics of cyclosporine in humans. Clin Pharmacol Ther. 2006 Mar;79(3):255-62. doi: 10.1016/j.clpt.2005.11.010. Epub 2006 Feb 7. PMID: 16513449.
  37. Dugrand-Judek A, Olry A, Hehn A, Costantino G, Ollitrault P, Froelicher Y, et al. (2015) The Distribution of Coumarins and Furanocoumarins in Citrus Species Closely Matches Citrus Phylogeny and Reflects the Organization of Biosynthetic Pathways. PLoS ONE 10(11): e0142757
  38. Gardana C, Nalin F, Simonetti P. Evaluation of flavonoids and furanocoumarins from Citrus bergamia (Bergamot) juice and identification of new compounds. Molecules. 2008 Sep 18;13(9):2220-8. doi: 10.3390/molecules13092220. PMID: 18830151; PMCID: PMC6244945.
  39. Alehaideb Z, Sheriffdeen M, Law FCP. Inhibition of Caffeine Metabolism by Apiaceous and Rutaceae Families of Plant Products in Humans: In Vivo and In VitroStudies. Front Pharmacol. 2021 Apr 29;12:641090. doi: 10.3389/fphar.2021.641090. PMID: 33995046; PMCID: PMC8116649.
  40. Maish WA, Hampton EM, Whitsett TL, Shepard JD, Lovallo WR. Influence of grapefruit juice on caffeine pharmacokinetics and pharmacodynamics. Pharmacotherapy. 1996 Nov-Dec;16(6):1046-52. PMID: 8947977.
  41. Verkerk R, Schreiner M, Krumbein A, Ciska E, Holst B, Rowland I, De Schrijver R, Hansen M, Gerhäuser C, Mithen R, Dekker M. Glucosinolates in Brassica vegetables: the influence of the food supply chain on intake, bioavailability and human health. Mol Nutr Food Res. 2009 Sep;53 Suppl 2:S219. doi: 10.1002/mnfr.200800065. PMID: 19035553.
  42. Campas-Baypoli ON, Bueno-Solano C, Martínez-Ibarra DM, Camacho-Gil F, Villa-Lerma AG, Rodríguez-Núñez JR, Lóez-Cervantes J, Sánchez-Machado DI. Contenido de sulforafano (1-isotiocianato-4-(metilsulfinil)-butano) en vegetales crucíferos [Sulforaphane (1-isothiocyanato-4-(methylsulfinyl)-butane) content in cruciferous vegetables]. Arch Latinoam Nutr. 2009 Mar;59(1):95-100. Spanish. PMID: 19480351.
  43. Chevolleau S, Gasc N, Rollin P, Tulliez J. Enzymatic, chemical, and thermal breakdown of 3H-labeled glucobrassicin, the parent indole glucosinolate.  JAgricFoodChem 1997; 45:4290-4296.
  44. Lubelska K, Milczarek M, Modzelewska K, Krzysztoń-Russjan J, Fronczyk K, Wiktorska K. Interactions between drugs and sulforaphane modulate the drug metabolism enzymatic system. Pharmacol Rep. 2012;64(5):1243-52. doi: 10.1016/s1734-1140(12)70920-9. PMID: 23238480.
  45. Shankar E, Goel A, Gupta K, Gupta S. Plant flavone apigenin: An emerging anticancer agent. Curr Pharmacol Rep. 2017;3(6):423-446. doi:10.1007/s40495-017-0113-2
  46. Svehlíková V, Wang S, Jakubíková J, Williamson G, Mithen R, Bao Y. Interactions between sulforaphane and apigenin in the induction of UGT1A1 and GSTA1 in CaCo-2 cells. Carcinogenesis. 2004 Sep;25(9):1629-37. doi: 10.1093/carcin/bgh169. Epub 2004 Apr 16. PMID: 15090468.
  47. Katchamart S, Stresser DM, Dehal SS, Kupfer D, Williams DE. Concurrent flavin-containing monooxygenase down-regulation and cytochrome P-450 induction by dietary indoles in rat: implications for drug-drug interaction. Drug Metab Dispos. 2000 Aug;28(8):930-6. PMID: 10901703.

Published September 9, 2023


About the Authors

Benton Bramwell, ND, is a 2002 graduate of National College of Naturopathic Medicine who practiced primarily in Utah while helping to expand the prescriptive rights of naturopathic physicians in that state.  Currently, he owns and operates Bramwell Partners, LLC, providing scientific and regulatory consulting services to both dietary supplement and conventional food companies.  He and his wife, Nanette, have six children and two grandchildren; they live in Manti, Utah.

Matt Warnock is an accidental herbalist, who received his MBA and Juris Doctor from BYU, then worked as an attorney, litigator, and business consultant until 2000. He then joined RidgeCrest Herbals, a family business started by his father, and started learning about
herbal medicine, focusing especially on complex herbal formulas. He has two U.S. patents for herbal formulations and methods. He lives near Salt Lake City with his wife, Carol; they are the parents of three children and four grandchildren.