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Potential Influence of Centrally Acting Herbal Drugs on Transporters at the Blood–Cerebrospinal Fluid Barrier and Blood–Brain Barrier

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Abstract

Complementary and alternative medications (CAM) with known or suspected pharmacologic activity in the central nervous system (CNS) are common. These herbal preparations may cause clinically significant drug–drug interactions (DDIs) when coadministered with medications that act in the CNS. This can result in negative outcomes such as toxicity or loss of efficacy. Most drug interaction reports with CAM focus on cytochrome P450 (CYP) modulation. However, drug interactions between CAM and conventional medications may occur via mechanisms other than CYP inhibition or induction; in particular, modulation of drug transport proteins represents an important mechanism by which such interactions may occur. This article provides an updated review of transporter-mediated mechanisms by which herbal products may theoretically interact with centrally acting medications at the blood–brain barrier and blood–cerebrospinal fluid (CSF) barrier. Further research is required before the true clinical impact of interactions involving modulation of centrally located membrane transporters can be fully understood.

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References

  1. Robinson MM, Zhang X. Traditional medicines: global situation, issues and challenges. The world medicines situation. 3rd ed. Geneva: WHO; 2011. p. 1–14.

    Google Scholar 

  2. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990–1997: results of a follow-up national survey. JAMA. 1998;280(18):1569–75.

    Article  CAS  Google Scholar 

  3. Strader DB, Bacon BR, Lindsay KL, et al. Use of complementary and alternative medicine in patients with liver disease. Am J Gastroenterol. 2002;97(9):2391–7. https://doi.org/10.1111/j.1572-0241.2002.05993.x.

    Article  PubMed  Google Scholar 

  4. Burstein HJ, Gelber S, Guadagnoli E, Weeks JC. Use of alternative medicine by women with early-stage breast cancer. N Engl J Med. 1999;340(22):1733–9. https://doi.org/10.1056/NEJM199906033402206.

    Article  CAS  PubMed  Google Scholar 

  5. Kassler WJ, Blanc P, Greenblatt R. The use of medicinal herbs by human immunodeficiency virus-infected patients. Arch Intern Med. 1991;151(11):2281–8.

    Article  CAS  Google Scholar 

  6. Blanc PD, Trupin L, Earnest G, Katz PP, Yelin EH, Eisner MD. Alternative therapies among adults with a reported diagnosis of asthma or rhinosinusitis: data from a population-based survey. Chest. 2001;120(5):1461–7.

    Article  CAS  Google Scholar 

  7. Bennett J, Brown CM. Use of herbal remedies by patients in a health maintenance organization. J Am Pharm Assoc Washington DC 1996. 2000;40(3):353–8.

    CAS  Google Scholar 

  8. The Office of Dietary Supplements. Dietary supplement health and education act of 1994. 1994. https://ods.od.nih.gov/About/DSHEA_Wording.aspx. Accessed 20 Feb 2018.

  9. Harkey MR, Henderson GL, Gershwin ME, Stern JS, Hackman RM. Variability in commercial ginseng products: an analysis of 25 preparations. Am J Clin Nutr. 2001;73(6):1101–6.

    Article  CAS  Google Scholar 

  10. Jann MW, Penzak SR, Cohen LJ. Applied clinical pharmacokinetics and pharmacodynamics of psychopharmacological agents. 1st ed. Cham: ADIS; 2016.

    Book  Google Scholar 

  11. Sanchez-Covarrubias L, Slosky LM, Thompson BJ, Davis TP, Ronaldson PT. Transporters at CNS barrier sites: obstacles or opportunities for drug delivery? Curr Pharm Des. 2014;20(10):1422–49.

    Article  CAS  Google Scholar 

  12. Chaves C, Shawahna R, Jacob A, Scherrmann J-M, Declèves X. Human ABC transporters at blood–CNS interfaces as determinants of CNS drug penetration. Curr Pharm Des. 2014;20(10):1450–62.

    Article  CAS  Google Scholar 

  13. Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV. Establishment and dysfunction of the blood–brain barrier. Cell. 2015;163(5):1064–78. https://doi.org/10.1016/j.cell.2015.10.067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fricker G. Drug interactions with natural products at the blood brain barrier. Curr Drug Metab. 2008;9(10):1019–26.

    Article  CAS  Google Scholar 

  15. Bennett DA, Phun L, Polk JF, Voglino SA, Zlotnik V, Raffa RB. Neuropharmacology of St. John’s Wort (Hypericum). Ann Pharmacother. 1998;32(11):1201–8. https://doi.org/10.1345/aph.18026.

    Article  PubMed  Google Scholar 

  16. Wurglics M, Schubert-Zsilavecz M. Hypericum perforatum: a “modern” herbal antidepressant: pharmacokinetics of active ingredients. Clin Pharmacokinet. 2006;45(5):449–68. https://doi.org/10.2165/00003088-200645050-00002.

    Article  CAS  PubMed  Google Scholar 

  17. Moore LB, Goodwin B, Jones SA, et al. St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA. 2000;97(13):7500–2. https://doi.org/10.1073/pnas.130155097.

    Article  CAS  PubMed  Google Scholar 

  18. Geick A, Eichelbaum M, Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem. 2001;276(18):14581–7. https://doi.org/10.1074/jbc.M010173200.

    Article  CAS  PubMed  Google Scholar 

  19. Hennessy M, Kelleher D, Spiers JP, et al. St Johns wort increases expression of P-glycoprotein: implications for drug interactions. Br J Clin Pharmacol. 2002;53(1):75–82.

    Article  CAS  Google Scholar 

  20. Li L, Stanton JD, Tolson AH, Luo Y, Wang H. Bioactive terpenoids and flavonoids from Ginkgo biloba extract induce the expression of hepatic drug-metabolizing enzymes through pregnane X receptor, constitutive androstane receptor, and aryl hydrocarbon receptor-mediated pathways. Pharm Res. 2009;26(4):872–82. https://doi.org/10.1007/s11095-008-9788-8.

    Article  CAS  PubMed  Google Scholar 

  21. Awortwe C, Manda VK, Avonto C, et al. Echinacea purpurea up-regulates CYP1A2, CYP3A4 and MDR1 gene expression by activation of pregnane X receptor pathway. Xenobiotica Fate Foreign Compd Biol Syst. 2015;45(3):218–29. https://doi.org/10.3109/00498254.2014.973930.

    Article  CAS  Google Scholar 

  22. Sugatani J, Uchida T, Kurosawa M, et al. Regulation of pregnane X receptor (PXR) function and UGT1A1 gene expression by posttranslational modification of PXR protein. Drug Metab Dispos Biol Fate Chem. 2012;40(10):2031–40. https://doi.org/10.1124/dmd.112.046748.

    Article  CAS  PubMed  Google Scholar 

  23. Rosenfeld JM, Vargas R, Xie W, Evans RM. Genetic profiling defines the xenobiotic gene network controlled by the nuclear receptor pregnane X receptor. Mol Endocrinol Baltim Md. 2003;17(7):1268–82. https://doi.org/10.1210/me.2002-0421.

    Article  CAS  Google Scholar 

  24. Barbenel DM, Yusufi B, O’Shea D, Bench CJ. Mania in a patient receiving testosterone replacement postorchidectomy taking St John’s wort and sertraline. J Psychopharmacol Oxf Engl. 2000;14(1):84–6. https://doi.org/10.1177/026988110001400113.

    Article  CAS  Google Scholar 

  25. Weiss J, Dormann S-MG, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, Haefeli WE. Inhibition of P-glycoprotein by newer antidepressants. J Pharmacol Exp Ther. 2003;305(1):197–204. https://doi.org/10.1124/jpet.102.046532.

    Article  CAS  PubMed  Google Scholar 

  26. Feng B, Mills JB, Davidson RE, et al. In vitro P-glycoprotein assays to predict the in vivo interactions of P-glycoprotein with drugs in the central nervous system. Drug Metab Dispos Biol Fate Chem. 2008;36(2):268–75. https://doi.org/10.1124/dmd.107.017434.

    Article  CAS  PubMed  Google Scholar 

  27. Wang J-S, Zhu H-J, Gibson BB, Markowitz JS, Donovan JL, DeVane CL. Sertraline and its metabolite desmethylsertraline, but not bupropion or its three major metabolites, have high affinity for P-glycoprotein. Biol Pharm Bull. 2008;31(2):231–4.

    Article  CAS  Google Scholar 

  28. Wang J-S, DeVane CL, Gibson BB, Donovan JL, Markowitz JS, Zhu H-J. Population pharmacokinetic analysis of drug–drug interactions among risperidone, bupropion, and sertraline in CF1 mice. Psychopharmacology. 2006;183(4):490–9. https://doi.org/10.1007/s00213-005-0209-y.

    Article  CAS  PubMed  Google Scholar 

  29. Dannawi M. Possible serotonin syndrome after combination of buspirone and St John’s Wort. J Psychopharmacol Oxf Engl. 2002;16(4):401. https://doi.org/10.1177/026988110201600420.

    Article  Google Scholar 

  30. Dinh LD, Simmen U, Bueter KB, Bueter B, Lundstrom K, Schaffner W. Interaction of various Piper methysticum cultivars with CNS receptors in vitro. Planta Med. 2001;67(4):306–11. https://doi.org/10.1055/s-2001-14334.

    Article  CAS  PubMed  Google Scholar 

  31. Owens C, Baergen R, Puckett D. Online sources of herbal product information. Am J Med. 2014;127(2):109–15. https://doi.org/10.1016/j.amjmed.2013.09.016.

    Article  PubMed  Google Scholar 

  32. Teschke R, Lebot V. Proposal for a kava quality standardization code. Food Chem Toxicol Int J Publ Br Ind Biol Res Assoc. 2011;49(10):2503–16. https://doi.org/10.1016/j.fct.2011.06.075.

    Article  CAS  Google Scholar 

  33. Li XZ, Ramzan I. Role of ethanol in kava hepatotoxicity. Phytother Res PTR. 2010;24(4):475–80. https://doi.org/10.1002/ptr.3046.

    Article  CAS  PubMed  Google Scholar 

  34. Teschke R, Gaus W, Loew D. Kava extracts: safety and risks including rare hepatotoxicity. Phytomed Int J Phytother Phytopharm. 2003;10(5):440–6. https://doi.org/10.1078/0944-7113-00314.

    Article  CAS  Google Scholar 

  35. Weiss J, Sauer A, Frank A, Unger M. Extracts and kavalactones of Piper methysticum G. Forst (kava-kava) inhibit P-glycoprotein in vitro. Drug Metab Dispos Biol Fate Chem. 2005;33(11):1580–3. https://doi.org/10.1124/dmd.105.005892.

    Article  CAS  PubMed  Google Scholar 

  36. Gurley BJ, Swain A, Barone GW, et al. Effect of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on digoxin pharmacokinetics in humans. Drug Metab Dispos Biol Fate Chem. 2007;35(2):240–5. https://doi.org/10.1124/dmd.106.012708.

    Article  CAS  PubMed  Google Scholar 

  37. Fromm MF, Kim RB, Stein CM, Wilkinson GR, Roden DM. Inhibition of P-glycoprotein-mediated drug transport: a unifying mechanism to explain the interaction between digoxin and quinidine [see comments]. Circulation. 1999;99(4):552–7.

    Article  CAS  Google Scholar 

  38. Rautio J, Humphreys JE, Webster LO, et al. In vitro p-glycoprotein inhibition assays for assessment of clinical drug interaction potential of new drug candidates: a recommendation for probe substrates. Drug Metab Dispos Biol Fate Chem. 2006;34(5):786–92. https://doi.org/10.1124/dmd.105.008615.

    Article  CAS  PubMed  Google Scholar 

  39. Foo H, Lemon J. Acute effects of kava, alone or in combination with alcohol, on subjective measures of impairment and intoxication and on cognitive performance. Drug Alcohol Rev. 1997;16(2):147–55. https://doi.org/10.1080/09595239700186441.

    Article  CAS  PubMed  Google Scholar 

  40. Almeida JC, Grimsley EW. Coma from the health food store: interaction between kava and alprazolam. Ann Intern Med. 1996;125(11):940–1.

    Article  CAS  Google Scholar 

  41. Jussofie A, Schmiz A, Hiemke C. Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain. Psychopharmacology. 1994;116(4):469–74.

    Article  CAS  Google Scholar 

  42. Mathews JM, Etheridge AS, Black SR. Inhibition of human cytochrome P450 activities by kava extract and kavalactones. Drug Metab Dispos Biol Fate Chem. 2002;30(11):1153–7.

    Article  CAS  Google Scholar 

  43. Yu D, Yuan Y, Jiang L, et al. Anti-inflammatory effects of essential oil in Echinacea purpurea L. Pak J Pharm Sci. 2013;26(2):403–8.

    PubMed  Google Scholar 

  44. Hellum BH, Nilsen OG. In vitro inhibition of CYP3A4 metabolism and P-glycoprotein-mediated transport by trade herbal products. Basic Clin Pharmacol Toxicol. 2008;102(5):466–75. https://doi.org/10.1111/j.1742-7843.2008.00227.x.

    Article  CAS  PubMed  Google Scholar 

  45. Gurley BJ, Swain A, Williams DK, Barone G, Battu SK. Gauging the clinical significance of P-glycoprotein-mediated herb–drug interactions: comparative effects of St. John’s wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics. Mol Nutr Food Res. 2008;52(7):772–9. https://doi.org/10.1002/mnfr.200700081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Penzak SR, Robertson SM, Hunt JD, et al. Echinacea purpurea significantly induces cytochrome P450 3A activity but does not alter lopinavir-ritonavir exposure in healthy subjects. Pharmacotherapy. 2010;30(8):797–805. https://doi.org/10.1592/phco.30.8.797.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Kaur S, Chhabra R, Nehru B. Ginkgo biloba extract attenuates hippocampal neuronal loss and cognitive dysfunction resulting from trimethyltin in mice. Phytomed Int J Phytother Phytopharm. 2013;20(2):178–86. https://doi.org/10.1016/j.phymed.2012.10.003.

    Article  CAS  Google Scholar 

  48. Robertson SM, Davey RT, Voell J, Formentini E, Alfaro RM, Penzak SR. Effect of Ginkgo biloba extract on lopinavir, midazolam and fexofenadine pharmacokinetics in healthy subjects. Curr Med Res Opin. 2008;24(2):591–9. https://doi.org/10.1185/030079908X260871.

    Article  CAS  PubMed  Google Scholar 

  49. Wang Y, Cao J, Zeng S. Involvement of P-glycoprotein in regulating cellular levels of Ginkgo flavonols: quercetin, kaempferol, and isorhamnetin. J Pharm Pharmacol. 2005;57(6):751–8. https://doi.org/10.1211/0022357056299.

    Article  CAS  PubMed  Google Scholar 

  50. Mandery K, Balk B, Bujok K, Schmidt I, Fromm MF, Glaeser H. Inhibition of hepatic uptake transporters by flavonoids. Eur J Pharm Sci Off J Eur Fed Pharm Sci. 2012;46(1–2):79–85. https://doi.org/10.1016/j.ejps.2012.02.014.

    Article  CAS  Google Scholar 

  51. Hajda J, Rentsch KM, Gubler C, Steinert H, Stieger B, Fattinger K. Garlic extract induces intestinal P-glycoprotein, but exhibits no effect on intestinal and hepatic CYP3A4 in humans. Eur J Pharm Sci Off J Eur Fed Pharm Sci. 2010;41(5):729–35. https://doi.org/10.1016/j.ejps.2010.09.016.

    Article  CAS  Google Scholar 

  52. Berginc K, Trdan T, Trontelj J, Kristl A. HIV protease inhibitors: garlic supplements and first-pass intestinal metabolism impact on the therapeutic efficacy. Biopharm Drug Dispos. 2010;31(8–9):495–505. https://doi.org/10.1002/bdd.730.

    Article  CAS  PubMed  Google Scholar 

  53. Piscitelli SC, Burstein AH, Welden N, Gallicano KD, Falloon J. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect Dis Off Publ Infect Dis Soc Am. 2002;34(2):234–8. https://doi.org/10.1086/324351.

    Article  Google Scholar 

  54. Duncan A, Mills J. An unusual case of HIV virologic failure during treatment with boosted atazanavir. AIDS Lond Engl. 2013;27(8):1361–2. https://doi.org/10.1097/QAD.0b013e32835fac84.

    Article  Google Scholar 

  55. Berginc K, Kristl A. The mechanisms responsible for garlic–drug interactions and their in vivo relevance. Curr Drug Metab. 2013;14(1):90–101.

    Article  CAS  Google Scholar 

  56. Berginc K, Zakelj S, Ursic D, Kristl A. Aged garlic extract stimulates p-glycoprotein and multidrug resistance associated protein 2 mediated effluxes. Biol Pharm Bull. 2009;32(4):694–9.

    Article  CAS  Google Scholar 

  57. Kim RB, Fromm MF, Wandel C, et al. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Investig. 1998;101(2):289–94. https://doi.org/10.1172/JCI1269.

    Article  CAS  PubMed  Google Scholar 

  58. Aquaro S, Svicher V, Ronga L, Perno CF, Pollicita M. HIV-1-associated dementia during HAART therapy. Recent Patents CNS Drug Discov. 2008;3(1):23–33.

    Article  CAS  Google Scholar 

  59. Hikino H, Konno C, Takata H, Tamada M. Antiinflammatory principle of ephedra herbs. Chem Pharm Bull (Tokyo). 1980;28(10):2900–4.

    Article  CAS  Google Scholar 

  60. Mantani N, Andoh T, Kawamata H, Terasawa K, Ochiai H. Inhibitory effect of Ephedrae herba, an oriental traditional medicine, on the growth of influenza A/PR/8 virus in MDCK cells. Antiviral Res. 1999;44(3):193–200.

    Article  CAS  Google Scholar 

  61. Shekelle PG, Hardy ML, Morton SC, et al. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis. JAMA. 2003;289(12):1537–45. https://doi.org/10.1001/jama.289.12.1537.

    Article  CAS  PubMed  Google Scholar 

  62. Zheng M, Zhou H, Wan H, Chen Y-L, He Y. Effects of herbal drugs in Mahuang decoction and their main components on intestinal transport characteristics of ephedra alkaloids evaluated by a Caco-2 cell monolayer model. J Ethnopharmacol. 2015;164:22–9. https://doi.org/10.1016/j.jep.2015.01.043.

    Article  CAS  PubMed  Google Scholar 

  63. Diepvens K, Westerterp KR, Westerterp-Plantenga MS. Obesity and thermogenesis related to the consumption of caffeine, ephedrine, capsaicin, and green tea. Am J Physiol Regul Integr Comp Physiol. 2007;292(1):R77–85. https://doi.org/10.1152/ajpregu.00832.2005.

    Article  CAS  PubMed  Google Scholar 

  64. Food and Drug Administration. 21 CFR part 119: Final rule declaring dietary supplements containing ephedrine alkaloids adulterated because they present an unreasonable risk. https://www.fda.gov/ohrms/dockets/98fr/04-2912.htm. Accessed 5 Oct 2017.

  65. Iwanaga K, Yoneda S, Hamahata Y, et al. Inhibitory effects of furanocoumarin derivatives in Kampo extract medicines on P-glycoprotein at the blood–brain barrier. Biol Pharm Bull. 2011;34(8):1246–51.

    Article  CAS  Google Scholar 

  66. Rizk ML, Zou L, Savic RM, Dooley KE. Importance of drug pharmacokinetics at the site of action. Clin Transl Sci. 2017;10(3):133–42. https://doi.org/10.1111/cts.12448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lee S-C, Arya V, Yang X, Volpe DA, Zhang L. Evaluation of transporters in drug development: current status and contemporary issues. Adv Drug Deliv Rev. 2017;116:100–18. https://doi.org/10.1016/j.addr.2017.07.020.

    Article  CAS  PubMed  Google Scholar 

  68. Sarris J, LaPorte E, Schweitzer I. Kava: a comprehensive review of efficacy, safety, and psychopharmacology. Aust N Z J Psychiatry. 2011;45(1):27–35. https://doi.org/10.3109/00048674.2010.522554.

    Article  Google Scholar 

  69. Jamieson DD, Duffield PH. The antinociceptive actions of kava components in mice. Clin Exp Pharmacol Physiol. 1990;17(7):495–507.

    Article  CAS  Google Scholar 

  70. Galeotti N. Hypericum perforatum (St John’s wort) beyond depression: a therapeutic perspective for pain conditions. J Ethnopharmacol. 2017;200:136–46. https://doi.org/10.1016/j.jep.2017.02.016.

    Article  CAS  PubMed  Google Scholar 

  71. Kasper S. Hypericum perforatum—a review of clinical studies. Pharmacopsychiatry. 2001;34(Suppl 1):S51–5.

    Article  CAS  Google Scholar 

  72. Vorbach EU, Arnoldt KH, Wolpert E. St John’s wort: a potential therapy for elderly depressed patients? Drugs Aging. 2000;16(3):189–97.

    Article  CAS  Google Scholar 

  73. Röder C, Schaefer M, Leucht S. Meta-analysis of effectiveness and tolerability of treatment of mild to moderate depression with St. John’s Wort. Fortschr Neurol Psychiatr. 2004;72(6):330–43. https://doi.org/10.1055/s-2003-812513.

    Article  PubMed  Google Scholar 

  74. He Y-T, Xing S-S, Gao L, Wang J, Xing Q-C, Zhang W. Ginkgo biloba attenuates oxidative DNA damage of human umbilical vein endothelial cells induced by intermittent high glucose. Pharm. 2014;69(3):203–7.

    CAS  Google Scholar 

  75. An G, Gallegos J, Morris ME. The bioflavonoid kaempferol is an Abcg2 substrate and inhibits Abcg2-mediated quercetin efflux. Drug Metab Dispos Biol Fate Chem. 2011;39(3):426–32. https://doi.org/10.1124/dmd.110.035212.

    Article  CAS  PubMed  Google Scholar 

  76. Fuchikami H, Satoh H, Tsujimoto M, Ohdo S, Ohtani H, Sawada Y. Effects of herbal extracts on the function of human organic anion-transporting polypeptide OATP-B. Drug Metab Dispos Biol Fate Chem. 2006;34(4):577–82. https://doi.org/10.1124/dmd.105.007872.

    Article  CAS  PubMed  Google Scholar 

  77. Fan L, Tao G-Y, Wang G, et al. Effects of Ginkgo biloba extract ingestion on the pharmacokinetics of talinolol in healthy Chinese volunteers. Ann Pharmacother. 2009;43(5):944–9. https://doi.org/10.1345/aph.1L656.

    Article  CAS  PubMed  Google Scholar 

  78. Fan L, Mao X-Q, Tao G-Y, et al. Effect of Schisandra chinensis extract and Ginkgo biloba extract on the pharmacokinetics of talinolol in healthy volunteers. Xenobiotica Fate Foreign Compd Biol Syst. 2009;39(3):249–54. https://doi.org/10.1080/00498250802687657.

    Article  CAS  Google Scholar 

  79. Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: an updated systematic review. Drugs. 2009;69(13):1777–98. https://doi.org/10.2165/11317010-000000000-00000.

    Article  CAS  PubMed  Google Scholar 

  80. Mancuso C, Santangelo R. Panax ginseng and Panax quinquefolius: from pharmacology to toxicology. Food Chem Toxicol Int J Publ Br Ind Biol Res Assoc. 2017;107(Pt A):362–72. https://doi.org/10.1016/j.fct.2017.07.019.

    Article  CAS  Google Scholar 

  81. Endale M, Lee WM, Kamruzzaman SM, et al. Ginsenoside-Rp1 inhibits platelet activation and thrombus formation via impaired glycoprotein VI signalling pathway, tyrosine phosphorylation and MAPK activation. Br J Pharmacol. 2012;167(1):109–27. https://doi.org/10.1111/j.1476-5381.2012.01967.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Boone SA, Shields KM. Treating pregnancy-related nausea and vomiting with ginger. Ann Pharmacother. 2005;39(10):1710–3. https://doi.org/10.1345/aph.1G086.

    Article  CAS  PubMed  Google Scholar 

  83. Sharifzadeh F, Kashanian M, Koohpayehzadeh J, Rezaian F, Sheikhansari N, Eshraghi N. A comparison between the effects of ginger, pyridoxine (vitamin B6) and placebo for the treatment of the first trimester nausea and vomiting of pregnancy (NVP). J Matern-Fetal Neonatal Med Off J Eur Assoc Perinat Med Fed Asia Ocean Perinat Soc Int Soc Perinat Obstet. 2017. https://doi.org/10.1080/14767058.2017.1344965.

    Article  Google Scholar 

  84. Viljoen E, Visser J, Koen N, Musekiwa A. A systematic review and meta-analysis of the effect and safety of ginger in the treatment of pregnancy-associated nausea and vomiting. Nutr J. 2014;13:20. https://doi.org/10.1186/1475-2891-13-20.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Srivastava KC. Aqueous extracts of onion, garlic and ginger inhibit platelet aggregation and alter arachidonic acid metabolism. Biomed Biochim Acta. 1984;43(8–9):S335–46.

    CAS  PubMed  Google Scholar 

  86. Xu J, Xu Z, Zheng W. A review of the antiviral role of green tea catechins. Mol Basel Switz. 2017. https://doi.org/10.3390/molecules22081337.

    Article  Google Scholar 

  87. Carini F, Tomasello G, Jurjus A, et al. Colorectal cancer and inflammatory bowel diseases: effects of diet and antioxidants. J Biol Regul Homeost Agents. 2017;31(3):791–5.

    CAS  PubMed  Google Scholar 

  88. Gomez-Pinilla F, Gomez AG. The influence of dietary factors in central nervous system plasticity and injury recovery. PM R. 2011;3(6 Suppl 1):S111–6. https://doi.org/10.1016/j.pmrj.2011.03.001.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Iciek M, Kwiecień I, Włodek L. Biological properties of garlic and garlic-derived organosulfur compounds. Environ Mol Mutagen. 2009;50(3):247–65. https://doi.org/10.1002/em.20474.

    Article  CAS  PubMed  Google Scholar 

  90. Nillert N, Pannangrong W, Welbat JU, Chaijaroonkhanarak W, Sripanidkulchai K, Sripanidkulchai B. Neuroprotective effects of aged garlic extract on cognitive dysfunction and neuroinflammation induced by β-amyloid in rats. Nutrients. 2017. https://doi.org/10.3390/nu9010024.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Bayan L, Koulivand PH, Gorji A. Garlic: a review of potential therapeutic effects. Avicenna J Phytomed. 2014;4(1):1–14.

    Article  Google Scholar 

  92. Resch KL, Ernst E. Garlic (Allium sativum)—a potent medicinal plant. Fortschr Med. 1995;113(20–21):311–5.

    CAS  PubMed  Google Scholar 

  93. Steiner M, Li W. Aged garlic extract, a modulator of cardiovascular risk factors: a dose-finding study on the effects of AGE on platelet functions. J Nutr. 2001;131(3s):980S–4S.

    Article  CAS  Google Scholar 

  94. Yeh YY, Liu L. Cholesterol-lowering effect of garlic extracts and organosulfur compounds: human and animal studies. J Nutr. 2001;131(3s):989S–93S.

    Article  CAS  Google Scholar 

  95. Kalix P. The pharmacology of psychoactive alkaloids from ephedra and catha. J Ethnopharmacol. 1991;32(1–3):201–8.

    Article  CAS  Google Scholar 

  96. Carlini EA. Plants and the central nervous system. Pharmacol Biochem Behav. 2003;75(3):501–12.

    Article  CAS  Google Scholar 

  97. Wuttke W, Jarry H, Haunschild J, Stecher G, Schuh M, Seidlova-Wuttke D. The non-estrogenic alternative for the treatment of climacteric complaints: black cohosh (Cimicifuga or Actaea racemosa). J Steroid Biochem Mol Biol. 2014;139:302–10. https://doi.org/10.1016/j.jsbmb.2013.02.007.

    Article  CAS  PubMed  Google Scholar 

  98. Borrelli F, Izzo AA, Ernst E. Pharmacological effects of Cimicifuga racemosa. Life Sci. 2003;73(10):1215–29.

    Article  CAS  Google Scholar 

  99. McKenna DJ, Jones K, Humphrey S, Hughes K. Black cohosh: efficacy, safety, and use in clinical and preclinical applications. Altern Ther Health Med. 2001;7(3):93–100.

    CAS  PubMed  Google Scholar 

  100. Lieberman S. A review of the effectiveness of Cimicifuga racemosa (black cohosh) for the symptoms of menopause. J Womens Health. 1998;7(5):525–9.

    Article  CAS  Google Scholar 

  101. Bundgaard C, Eneberg E, Sánchez C. P-glycoprotein differentially affects escitalopram, levomilnacipran, vilazodone and vortioxetine transport at the mouse blood–brain barrier in vivo. Neuropharmacology. 2016;103:104–11. https://doi.org/10.1016/j.neuropharm.2015.12.009.

    Article  CAS  PubMed  Google Scholar 

  102. Bhuiyan M, Petropoulos S, Gibb W, Matthews SG. Sertraline alters multidrug resistance phosphoglycoprotein activity in the mouse placenta and fetal blood–brain barrier. Reprod Sci Thousand Oaks Calif. 2012;19(4):407–15. https://doi.org/10.1177/1933719111424438.

    Article  CAS  Google Scholar 

  103. Bachmeier C, Levin GM, Beaulieu-Abdelahad D, Reed J, Mullan M. Effect of venlafaxine and desvenlafaxine on drug efflux protein expression and biodistribution in vivo. J Pharm Sci. 2013;102(10):3838–43. https://doi.org/10.1002/jps.23680.

    Article  CAS  PubMed  Google Scholar 

  104. O’Brien FE, Clarke G, Dinan TG, Cryan JF, Griffin BT. Human P-glycoprotein differentially affects antidepressant drug transport: relevance to blood–brain barrier permeability. Int J Neuropsychopharmacol. 2013;16(10):2259–72. https://doi.org/10.1017/S1461145713000692.

    Article  CAS  PubMed  Google Scholar 

  105. Nagasaka Y, Sano T, Oda K, Kawamura A, Usui T. Impact of genetic deficiencies of P-glycoprotein and breast cancer resistance protein on pharmacokinetics of aripiprazole and dehydroaripiprazole. Xenobiotica Fate Foreign Compd Biol Syst. 2014;44(10):926–32. https://doi.org/10.3109/00498254.2014.901585.

    Article  CAS  Google Scholar 

  106. Holthoewer D, Kirschbaum KM, Frisch J, Hiemke C, Schmitt U. Pharmacodynamic effects of aripiprazole and ziprasidone with respect to p-glycoprotein substrate properties. Pharmacopsychiatry. 2013;46(5):175–80. https://doi.org/10.1055/s-0033-1347176.

    Article  CAS  PubMed  Google Scholar 

  107. Wang J-S, Zhu H-J, Markowitz JS, Donovan JL, Yuan H-J, Devane CL. Antipsychotic drugs inhibit the function of breast cancer resistance protein. Basic Clin Pharmacol Toxicol. 2008;103(4):336–41. https://doi.org/10.1111/j.1742-7843.2008.00298.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Chen C, Hanson E, Watson JW, Lee JS. P-glycoprotein limits the brain penetration of nonsedating but not sedating H1-antagonists. Drug Metab Dispos Biol Fate Chem. 2003;31(3):312–8.

    Article  CAS  Google Scholar 

  109. Schinkel AH, Wagenaar E, Mol CA, van Deemter L. P-glycoprotein in the blood–brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Investig. 1996;97(11):2517–24. https://doi.org/10.1172/JCI118699.

    Article  CAS  PubMed  Google Scholar 

  110. Ochiai W, Kaneta M, Nagae M, et al. Mice with neuropathic pain exhibit morphine tolerance due to a decrease in the morphine concentration in the brain. Eur J Pharm Sci. 2016;92:298–304. https://doi.org/10.1016/j.ejps.2016.03.019.

    Article  CAS  PubMed  Google Scholar 

  111. Römermann K, Helmer R, Löscher W. The antiepileptic drug lamotrigine is a substrate of mouse and human breast cancer resistance protein (ABCG2). Neuropharmacology. 2015;93:7–14. https://doi.org/10.1016/j.neuropharm.2015.01.015.

    Article  CAS  PubMed  Google Scholar 

  112. Ma A, Wang C, Chen Y, Yuan W. P-glycoprotein alters blood–brain barrier penetration of antiepileptic drugs in rats with medically intractable epilepsy. Drug Des Devel Ther. 2013;7:1447–54. https://doi.org/10.2147/DDDT.S52533.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Nakanishi H, Yonezawa A, Matsubara K, Yano I. Impact of P-glycoprotein and breast cancer resistance protein on the brain distribution of antiepileptic drugs in knockout mouse models. Eur J Pharmacol. 2013;710(1–3):20–8. https://doi.org/10.1016/j.ejphar.2013.03.049.

    Article  CAS  PubMed  Google Scholar 

  114. Vautier S, Milane A, Fernandez C, Buyse M, Chacun H, Farinotti R. Interactions between antiparkinsonian drugs and ABCB1/P-glycoprotein at the blood–brain barrier in a rat brain endothelial cell model. Neurosci Lett. 2008;442(1):19–23. https://doi.org/10.1016/j.neulet.2008.06.055.

    Article  CAS  PubMed  Google Scholar 

  115. Takeuchi R, Shinozaki K, Nakanishi T, Tamai I. Local drug–drug interaction of donepezil with cilostazol at breast cancer resistance protein (ABCG2) increases drug accumulation in heart. Drug Metab Dispos Biol Fate Chem. 2016;44(1):68–74. https://doi.org/10.1124/dmd.115.066654.

    Article  CAS  PubMed  Google Scholar 

  116. Nabekura T, Yamaki T, Ueno K, Kitagawa S. Inhibition of P-glycoprotein and multidrug resistance protein 1 by dietary phytochemicals. Cancer Chemother Pharmacol. 2008;62(5):867–73. https://doi.org/10.1007/s00280-007-0676-4.

    Article  CAS  PubMed  Google Scholar 

  117. Turkanovic J, Ward MB, Gerber JP, Milne RW. Effect of garlic, gingko, and St. John’s Wort extracts on the pharmacokinetics of fexofenadine: a mechanistic study. Drug Metab Dispos Biol Fate Chem. 2017;45(5):569–75. https://doi.org/10.1124/dmd.116.073528.

    Article  CAS  PubMed  Google Scholar 

  118. Jendželovská Z, Jendželovský R, Hiľovská L, Kovaľ J, Mikeš J, Fedoročko P. Single pre-treatment with hypericin, a St. John’s wort secondary metabolite, attenuates cisplatin- and mitoxantrone-induced cell death in A2780, A2780cis and HL-60 cells. Toxicol Vitro Int J Publ Assoc BIBRA. 2014;28(7):1259–73. https://doi.org/10.1016/j.tiv.2014.06.011.

    Article  CAS  Google Scholar 

  119. Schulte-Löbbert S, Holoubek G, Müller WE, Schubert-Zsilavecz M, Wurglics M. Comparison of the synaptosomal uptake inhibition of serotonin by St John’s wort products. J Pharm Pharmacol. 2004;56(6):813–8. https://doi.org/10.1211/0022357023493.

    Article  CAS  PubMed  Google Scholar 

  120. Asher GN, Corbett AH, Hawke RL. Common herbal dietary supplement-drug interactions. Am Fam Physician. 2017;96(2):101–7.

    PubMed  Google Scholar 

  121. Hansen TS, Nilsen OG. Echinacea purpurea and P-glycoprotein drug transport in Caco-2 cells. Phytother Res PTR. 2009;23(1):86–91. https://doi.org/10.1002/ptr.2563.

    Article  PubMed  Google Scholar 

  122. Choi C-H, Kang G, Min Y-D. Reversal of P-glycoprotein-mediated multidrug resistance by protopanaxatriol ginsenosides from Korean red ginseng. Planta Med. 2003;69(3):235–40. https://doi.org/10.1055/s-2003-38483.

    Article  CAS  PubMed  Google Scholar 

  123. Jin J, Shahi S, Kang HK, van Veen HW, Fan T-P. Metabolites of ginsenosides as novel BCRP inhibitors. Biochem Biophys Res Commun. 2006;345(4):1308–14. https://doi.org/10.1016/j.bbrc.2006.04.152.

    Article  CAS  PubMed  Google Scholar 

  124. Nabekura T, Kamiyama S, Kitagawa S. Effects of dietary chemopreventive phytochemicals on P-glycoprotein function. Biochem Biophys Res Commun. 2005;327(3):866–70. https://doi.org/10.1016/j.bbrc.2004.12.081.

    Article  CAS  PubMed  Google Scholar 

  125. Jodoin J, Demeule M, Beliveau R. Inhibition of the multidrug resistance P-glycoprotein activity by green tea polyphenols. Biochim Biophys Acta. 2002;1542(1–3):149–59.

    Article  CAS  Google Scholar 

  126. Knop J, Misaka S, Singer K, et al. Inhibitory effects of green tea and (-)-epigallocatechin gallate on transport by OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2-K and P-Glycoprotein. PLoS One. 2015;10(10):e0139370. https://doi.org/10.1371/journal.pone.0139370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Fleisher B, Unum J, Shao J, An G. Ingredients in fruit juices interact with dasatinib through inhibition of BCRP: a new mechanism of beverage–drug interaction. J Pharm Sci. 2015;104(1):266–75. https://doi.org/10.1002/jps.24289.

    Article  CAS  PubMed  Google Scholar 

  128. Netsch MI, Gutmann H, Luescher S, et al. Inhibitory activity of a green tea extract and some of its constituents on multidrug resistance-associated protein 2 functionality. Planta Med. 2005;71(2):135–41. https://doi.org/10.1055/s-2005-837780.

    Article  CAS  PubMed  Google Scholar 

  129. Zhang S, Morris ME. Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P-glycoprotein-mediated transport. J Pharmacol Exp Ther. 2003;304(3):1258–67. https://doi.org/10.1124/jpet.102.044412.

    Article  CAS  PubMed  Google Scholar 

  130. Tamaki H, Satoh H, Hori S, Ohtani H, Sawada Y. Inhibitory effects of herbal extracts on breast cancer resistance protein (BCRP) and structure-inhibitory potency relationship of isoflavonoids. Drug Metab Pharmacokinet. 2010;25(2):170–9.

    Article  CAS  Google Scholar 

  131. Xin Y, Yin F, Qi S, et al. Parthenolide reverses doxorubicin resistance in human lung carcinoma A549 cells by attenuating NF-κB activation and HSP70 up-regulation. Toxicol Lett. 2013;221(2):73–82. https://doi.org/10.1016/j.toxlet.2013.06.215.

    Article  CAS  PubMed  Google Scholar 

  132. Gurley BJ, Barone GW, Williams DK, et al. Effect of milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa) supplementation on digoxin pharmacokinetics in humans. Drug Metab Dispos Biol Fate Chem. 2006;34(1):69–74. https://doi.org/10.1124/dmd.105.006312.

    Article  CAS  PubMed  Google Scholar 

  133. Lown KS, Mayo RR, Leichtman AB, et al. Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther. 1997;62(3):248–60. https://doi.org/10.1016/S0009-9236(97)90027-8.

    Article  CAS  PubMed  Google Scholar 

  134. Edwards DJ, Fitzsimmons ME, Schuetz EG, et al. 6′,7′-Dihydroxybergamottin in grapefruit juice and Seville orange juice: effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein. Clin Pharmacol Ther. 1999;65(3):237–44. https://doi.org/10.1016/S0009-9236(99)70102-5.

    Article  CAS  PubMed  Google Scholar 

  135. Ohnishi A, Matsuo H, Yamada S, et al. Effect of furanocoumarin derivatives in grapefruit juice on the uptake of vinblastine by Caco-2 cells and on the activity of cytochrome P450 3A4. Br J Pharmacol. 2000;130(6):1369–77. https://doi.org/10.1038/sj.bjp.0703433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. de Castro WV, Mertens-Talcott S, Derendorf H, Butterweck V. Grapefruit juice–drug interactions: grapefruit juice and its components inhibit P-glycoprotein (ABCB1) mediated transport of talinolol in Caco-2 cells. J Pharm Sci. 2007;96(10):2808–17. https://doi.org/10.1002/jps.20975.

    Article  CAS  PubMed  Google Scholar 

  137. Paine MF, Widmer WW, Pusek SN, et al. Further characterization of a furanocoumarin-free grapefruit juice on drug disposition: studies with cyclosporine. Am J Clin Nutr. 2008;87(4):863–71.

    Article  CAS  Google Scholar 

  138. Dahan A, Amidon GL. Grapefruit juice and its constituents augment colchicine intestinal absorption: potential hazardous interaction and the role of p-glycoprotein. Pharm Res. 2009;26(4):883–92. https://doi.org/10.1007/s11095-008-9789-7.

    Article  CAS  PubMed  Google Scholar 

  139. Peltoniemi MA, Saari TI, Hagelberg NM, Laine K, Neuvonen PJ, Olkkola KT. St John’s wort greatly decreases the plasma concentrations of oral S-ketamine. Fundam Clin Pharmacol. 2012;26(6):743–50. https://doi.org/10.1111/j.1472-8206.2011.00954.x.

    Article  CAS  PubMed  Google Scholar 

  140. Hojo Y, Echizenya M, Ohkubo T, Shimizu T. Drug interaction between St John’s wort and zolpidem in healthy subjects. J Clin Pharm Ther. 2011;36(6):711–5. https://doi.org/10.1111/j.1365-2710.2010.01223.x.

    Article  CAS  PubMed  Google Scholar 

  141. Lei H-P, Yu X-Y, Xie H-T, et al. Effect of St. John’s wort supplementation on the pharmacokinetics of bupropion in healthy male Chinese volunteers. Xenobiotica Fate Foreign Compd Biol Syst. 2010;40(4):275–81. https://doi.org/10.3109/00498250903509383.

    Article  CAS  Google Scholar 

  142. Nieminen TH, Hagelberg NM, Saari TI, et al. St John’s wort greatly reduces the concentrations of oral oxycodone. Eur J Pain Lond Engl. 2010;14(8):854–9. https://doi.org/10.1016/j.ejpain.2009.12.007.

    Article  CAS  Google Scholar 

  143. Wang Z, Hamman MA, Huang S-M, Lesko LJ, Hall SD. Effect of St John’s wort on the pharmacokinetics of fexofenadine. Clin Pharmacol Ther. 2002;71(6):414–20. https://doi.org/10.1067/mcp.2002.124080.

    Article  CAS  PubMed  Google Scholar 

  144. Dresser GK, Schwarz UI, Wilkinson GR, Kim RB. Coordinate induction of both cytochrome P4503A and MDR1 by St John’s wort in healthy subjects. Clin Pharmacol Ther. 2003;73(1):41–50. https://doi.org/10.1067/mcp.2003.10.

    Article  CAS  PubMed  Google Scholar 

  145. Johne A, Schmider J, Brockmöller J, et al. Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John’s wort (Hypericum perforatum). J Clin Psychopharmacol. 2002;22(1):46–54.

    Article  CAS  Google Scholar 

  146. Asdaq SMB, Inamdar MN. Pharmacodynamic and pharmacokinetic interactions of propranolol with garlic (Allium sativum) in rats. Evid Based Complement Altern Med ECAM. 2011;2011:824042. https://doi.org/10.1093/ecam/neq076.

    Article  Google Scholar 

  147. Markowitz JS, Devane CL, Chavin KD, Taylor RM, Ruan Y, Donovan JL. Effects of garlic (Allium sativum L.) supplementation on cytochrome P450 2D6 and 3A4 activity in healthy volunteers. Clin Pharmacol Ther. 2003;74(2):170–7. https://doi.org/10.1016/S0009-9236(03)00148-6.

    Article  CAS  PubMed  Google Scholar 

  148. Gurley BJ, Gardner SF, Hubbard MA, et al. Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St John’s wort, garlic oil, Panax ginseng and Ginkgo biloba. Drugs Aging. 2005;22(6):525–39.

    Article  CAS  Google Scholar 

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  1. Clinical Pharmacokinetics Research Unit, Clinical Center Pharmacy Department, National Institutes of Health (NIH), Bethesda, MD, USA

    Lilian W. Kibathi & Parag Kumar

  2. University of Iowa College of Pharmacy, Iowa City, IA, USA

    SoHyun Bae

  3. Department of Pharmacotherapy, University of North Texas System, College of Pharmacy, 3500 Camp Bowie Blvd-RES 302B, Fort Worth, TX, 76107, USA

    Scott R. Penzak

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Kibathi, L.W., Bae, S., Penzak, S.R. et al. Potential Influence of Centrally Acting Herbal Drugs on Transporters at the Blood–Cerebrospinal Fluid Barrier and Blood–Brain Barrier. Eur J Drug Metab Pharmacokinet 43, 619–635 (2018). https://doi.org/10.1007/s13318-018-0486-6

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