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  1. Article: Cytochrome P450 enzyme mediated herbal drug interactions (Part 1).

    Wanwimolruk, Sompon / Prachayasittikul, Virapong

    EXCLI journal

    2014  Volume 13, Page(s) 347–391

    Abstract: ... several significant herbal drug interactions have their origins in the alteration of CYP enzyme activity by various ... induction of the metabolism of drugs catalyzed by the important enzymes, cytochrome P450 (CYP). The aim ... risk for adverse herbal drug interactions. Such interactions can enhance the risk for an individual ...

    Abstract It is well recognized that herbal supplements or herbal medicines are now commonly used. As many patients taking prescription medications are concomitantly using herbal supplements, there is considerable risk for adverse herbal drug interactions. Such interactions can enhance the risk for an individual patient, especially with regard to drugs with a narrow therapeutic index such as warfarin, cyclosporine A and digoxin. Herbal drug interactions can alter pharmacokinetic or/and pharmacodynamic properties of administered drugs. The most common pharmacokinetic interactions usually involve either the inhibition or induction of the metabolism of drugs catalyzed by the important enzymes, cytochrome P450 (CYP). The aim of the present article is to provide an updated review of clinically relevant metabolic CYP-mediated drug interactions between selected herbal supplements and prescription drugs. The commonly used herbal supplements selected include Echinacea, Ginkgo biloba, garlic, St. John's wort, goldenseal, and milk thistle. To date, several significant herbal drug interactions have their origins in the alteration of CYP enzyme activity by various phytochemicals. Numerous herbal drug interactions have been reported. Although the significance of many interactions is uncertain but several interactions, especially those with St. John's wort, may have critical clinical consequences. St. John's wort is a source of hyperforin, an active ingredient that has a strong affinity for the pregnane xenobiotic receptor (PXR). As a PXR ligand, hyperforin promotes expression of CYP3A4 enzymes in the small intestine and liver. This in turn causes induction of CYP3A4 and can reduce the oral bioavailability of many drugs making them less effective. The available evidence indicates that, at commonly recommended doses, other selected herbs including Echinacea, Ginkgo biloba, garlic, goldenseal and milk thistle do not act as potent or moderate inhibitors or inducers of CYP enzymes. A good knowledge of the mechanisms of herbal drug interactions is necessary for assessing and minimizing clinical risks. These processes help prediction of interactions between herbal supplements and prescription drugs. Healthcare professionals should remain vigilant for potential interactions between herbal supplements/medicines and prescription drugs, especially for drugs with a narrow therapeutic index are used.
    Language English
    Publishing date 2014-04-02
    Publishing country Germany
    Document type Journal Article ; Review
    ISSN 1611-2156
    ISSN 1611-2156
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Heterotropic activation of flavonoids on cytochrome P450 3A4: A case example of alleviating dronedarone-induced cytotoxicity.

    Bai, Jie / Li, Li / Zhao, Shengyu / Fan, Xiaoqing / Zhang, Jie / Hu, Minwan / Chen, Yonghui / Sun, Yanhong / Wang, Baolian / Jin, Jing / Wang, Xiaojian / Zhang, Dan / Hu, Jinping / Li, Yan

    Toxicology letters

    2019  Volume 319, Page(s) 187–196

    Abstract: The clinical drug-drug interactions mediated by heterotropic activation on cytochrome P450 (CYP450 ... The frequent and numerous uses of flavonoids may increase the risk of food/herb-drug interactions ... of flavonoid-containing food/herb-drug interactions in humans. ...

    Abstract The clinical drug-drug interactions mediated by heterotropic activation on cytochrome P450 (CYP450) kinetics, especially CYP3A4, have received wide concern in recent years. Flavonoids, a group of important natural substances with various pharmacological activities, distribute widely among vegetables, fruits and herbs. The frequent and numerous uses of flavonoids may increase the risk of food/herb-drug interactions. However, little is known about activation effects of flavonoids on CYP3A4. The aim of this study was to investigate activation of CYP3A4 by flavonoids, explore the molecular mechanism, and assess the biological effects on dronedarone (DND) induced toxicity. The results showed that flavone, tangeretin, sinensetin and 6-hydroxyflavone increased the cell viability by decreasing DND-induced cytotoxicity. These four flavonoids could activate the metabolism of DND in hamster pharmacokinetics study. Furthermore, both molecular docking and circular dichroism analysis partially illustrated the molecular mechanism of heterotropic activation. Finally, the pharmacophore model suggested B aromatic ring, hydrophobic groups at 7-position and hydrogen bond acceptors at 4-position may play a vital role in activation of flavonoids on CYP3A4. Taken together, our findings would provide useful information for predicting the potential risks of flavonoid-containing food/herb-drug interactions in humans.
    MeSH term(s) Animals ; Anti-Arrhythmia Agents/pharmacokinetics ; Anti-Arrhythmia Agents/toxicity ; Cell Survival/drug effects ; Circular Dichroism ; Cricetinae ; Cytochrome P-450 CYP3A/metabolism ; Dronedarone/pharmacokinetics ; Dronedarone/toxicity ; Enzyme Activation ; Enzyme Activators/pharmacology ; Flavonoids/pharmacology ; Herb-Drug Interactions ; Hydrogen Bonding ; Male ; Mesocricetus ; Models, Molecular ; Molecular Docking Simulation
    Chemical Substances Anti-Arrhythmia Agents ; Enzyme Activators ; Flavonoids ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; Dronedarone (JQZ1L091Y2)
    Language English
    Publishing date 2019-11-19
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 433788-8
    ISSN 1879-3169 ; 0378-4274
    ISSN (online) 1879-3169
    ISSN 0378-4274
    DOI 10.1016/j.toxlet.2019.11.016
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Cytochrome P450 enzyme mediated herbal drug interactions (Part 2).

    Wanwimolruk, Sompon / Phopin, Kamonrat / Prachayasittikul, Virapong

    EXCLI journal

    2014  Volume 13, Page(s) 869–896

    Abstract: To date, a number of significant herbal drug interactions have their origins in the alteration ... on herbal drug interactions. These include black cohosh, ginseng, grape seed extract, green tea, kava, saw palmetto and ... of herbal drug interactions. It appeared that the majority of the herbal medicines have no clear effects on most of the CYPs ...

    Abstract To date, a number of significant herbal drug interactions have their origins in the alteration of cytochrome P450 (CYP) activity by various phytochemicals. Among the most noteworthy are those involving St. John's wort and drugs metabolized by human CYP3A4 enzyme. This review article is the continued work from our previous article (Part 1) published in this journal (Wanwimolruk and Prachayasittikul, 2014[ref:133]). This article extends the scope of the review to six more herbs and updates information on herbal drug interactions. These include black cohosh, ginseng, grape seed extract, green tea, kava, saw palmetto and some important Chinese medicines are also presented. Even though there have been many studies to determine the effects of herbs and herbal medicines on the activity of CYP, most of them were in vitro and in animal studies. Therefore, the studies are limited in predicting the clinical relevance of herbal drug interactions. It appeared that the majority of the herbal medicines have no clear effects on most of the CYPs examined. For example, the existing clinical trial data imply that black cohosh, ginseng and saw palmetto are unlikely to affect the pharmacokinetics of conventional drugs metabolized by human CYPs. For grape seed extract and green tea, adverse herbal drug interactions are unlikely when they are concomitantly taken with prescription drugs that are CYP substrates. Although there were few clinical studies on potential CYP-mediated interactions produced by kava, present data suggest that kava supplements have the ability to inhibit CYP1A2 and CYP2E1 significantly. Therefore, caution should be taken when patients take kava with CYP1A2 or CYP2E1 substrate drugs as it may enhance their therapeutic and adverse effects. Despite the long use of traditional Chinese herbal medicines, little is known about the potential drug interactions with these herbs. Many popularly used Chinese medicines have been shown in vitro to significantly change the activity of human CYP. However, with little confirming evidence from clinical studies, precaution should be exercised when patients are taking Chinese herbal medicines concomitantly with drugs that are CYP substrates. Currently there is sufficient evidence to indicate that herbal drug interactions can occur and may lead to serious clinical consequence. Further clinical trial research should be conducted to verify these herbal drug interactions. Education on herbal drug interactions and communication with patients on their use of herbal products is also important.
    Language English
    Publishing date 2014-08-20
    Publishing country Germany
    Document type Journal Article ; Review
    ISSN 1611-2156
    ISSN 1611-2156
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: 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.

    Gurley, Bill J / Gardner, Stephanie F / Hubbard, Martha A / Williams, D Keith / Gentry, W Brooks / Cui, Yanyan / Ang, Catharina Y W

    Drugs & aging

    2005  Volume 22, Issue 6, Page(s) 525–539

    Abstract: ... modulation of cytochrome P450 (CYP) activity may underlie many herb-drug interactions. Some evidence suggests ... with botanical supplements, and may therefore be vulnerable to herb-drug interactions. Phytochemical-mediated ... their younger counterparts, are susceptible to herb-mediated changes in CYP activity, especially those involving ...

    Abstract Objectives: Elderly patients are more likely to ingest prescription medications concurrently with botanical supplements, and may therefore be vulnerable to herb-drug interactions. Phytochemical-mediated modulation of cytochrome P450 (CYP) activity may underlie many herb-drug interactions. Some evidence suggests that CYP activity may decrease in the elderly. If so, herb-mediated changes in CYP activity may take on greater clinical relevance in this population. In this study, single timepoint, phenotypic metabolic ratios were used to determine whether long-term supplementation of St John's wort, garlic oil, Panax ginseng, and Ginkgo biloba affected CYP1A2, CYP2D6, CYP2E1 or CYP3A4 activity in elderly subjects.
    Methods: Twelve healthy volunteers between the ages of 60 and 76 years (mean age 67 years) were randomly assigned to receive each botanical supplement for 28 days followed by a 30-day washout period. Probe drug cocktails of midazolam, caffeine, chlorzoxazone and debrisoquine were administered before and at the end of supplementation. Pre- and post-supplementation phenotypic ratios were determined for CYP3A4, CYP1A2, CYP2E1 and CYP2D6 using 1-hydroxymidazolam/midazolam serum ratios (1-hour), paraxanthine/caffeine serum ratios (6-hour), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour) and debrisoquine urinary recovery ratios (8-hour), respectively. The content of purported 'active' phytochemicals was determined for each supplement.
    Results: Comparisons of pre- and post-St John's wort phenotypic ratios revealed significant induction of CYP3A4 (approximately 140%) and CYP2E1 activity (approximately 28%). Garlic oil inhibited CYP2E1 activity by approximately 22%. P. ginseng inhibition of CYP2D6 was statistically significant, but the magnitude of the effect (approximately 7%) did not appear to be clinically relevant. None of the supplements tested in this study appeared to affect CYP1A2 activity.
    Conclusions: Elderly subjects, like their younger counterparts, are susceptible to herb-mediated changes in CYP activity, especially those involving St John's wort. Pharmacokinetic herb-drug interactions stemming from alterations in CYP activity may adversely affect drug efficacy and/or toxicity. When compared with earlier studies that employed young subjects, the data suggest that some age-related changes in CYP responsivity to botanical supplementation may exist. Concomitant ingestion of botanical supplements with prescription medications, therefore, should be strongly discouraged in the elderly.
    MeSH term(s) Administration, Oral ; Aged ; Allyl Compounds/chemistry ; Caffeine/administration & dosage ; Caffeine/blood ; Caffeine/pharmacology ; Chlorzoxazone/administration & dosage ; Chlorzoxazone/blood ; Chlorzoxazone/pharmacology ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System/genetics ; Cytochrome P-450 Enzyme System/metabolism ; Dietary Supplements ; Drug Administration Schedule ; Female ; Ginkgo biloba/chemistry ; Herb-Drug Interactions ; Humans ; Hypericum/chemistry ; Isoenzymes/antagonists & inhibitors ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Male ; Midazolam/administration & dosage ; Midazolam/blood ; Midazolam/pharmacology ; Panax/chemistry ; Phenotype ; Plant Preparations/administration & dosage ; Plant Preparations/chemistry ; Plant Preparations/pharmacology ; Sulfides/chemistry
    Chemical Substances Allyl Compounds ; Cytochrome P-450 Enzyme Inhibitors ; Isoenzymes ; Plant Preparations ; Sulfides ; Caffeine (3G6A5W338E) ; allyl sulfide (60G7CF7CWZ) ; Cytochrome P-450 Enzyme System (9035-51-2) ; Chlorzoxazone (H0DE420U8G) ; Midazolam (R60L0SM5BC)
    Language English
    Publishing date 2005-09-01
    Publishing country New Zealand
    Document type Comparative Study ; Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 1075770-3
    ISSN 1179-1969 ; 1170-229X
    ISSN (online) 1179-1969
    ISSN 1170-229X
    DOI 10.2165/00002512-200522060-00006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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