An in vitro Evaluation of Cytochrome P450 Inhibition and P-Glycoprotein Interaction with Goldenseal, Ginkgo biloba , Grape Seed, Milk Thistle, and Ginseng Extracts and Their Constituents

RTI International, Durham, North Carolina, United States
Planta Medica (Impact Factor: 2.15). 07/2007; 73(8):731-41. DOI: 10.1055/s-2007-981550
Source: PubMed


Drug-herb interactions can result from the modulation of the activities of cytochrome P450 (P450) and/or drug transporters. The effect of extracts and individual constituents of goldenseal, Ginkgo biloba (and its hydrolyzate), grape seed, milk thistle, and ginseng on the activities of cytochrome P450 enzymes CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 in human liver microsomes were determined using enzyme-selective probe substrates, and their effect on human P-glycoprotein (Pgp) was determined using a baculovirus expression system by measuring the verapamil-stimulated, vanadate-sensitive ATPase activity. Extracts were analyzed by HPLC to standardize their concentration(s) of constituents associated with the pharmacological activity, and to allow comparison of their effects on P450 and Pgp with literature values. Many of the extracts/constituents exerted > or = 50 % inhibition of P450 activity. These include those from goldenseal (normalized to alkaloid content) inhibiting CYP2C8, CYP2D6, and CYP3A4 at 20 microM, ginkgo inhibiting CYP2C8 at 10 microM, grape seed inhibiting CYP2C9 and CYP3A4 at 10 microM, milk thistle inhibiting CYP2C8 at 10 microM, and ginsenosides F1 and Rh1 (but not ginseng extract) inhibiting CYP3A4 at 10 microM. Goldenseal extracts/constituents (20 microM, particularly hydrastine) and ginsenoside Rh1 stimulated ATPase at about half of the activity of the model substrate, verapamil (20 microM). The data suggest that the clearance of a variety of drugs may be diminished by concomitant use of these herbs via inhibition of P450 enzymes, but less so by Pgp-mediated effects.

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    • "However, hydrastine (consisting of (-)-β-hydrastine and (-)-α-hydrastine ) and berberine are generally believed to be the two principal bioactive components (Abourashed and Khan, 2001). Several in vitro studies have demonstrated that both GS extracts and individual alkaloids can inhibit CYP2C9, 2D6, and 3A4 activity (Chatterjee and Franklin, 2003; Etheridge et al., 2007)a n das i g n i ficant inhibitory effect of GS on CYP2D6 and CYP 3A4/5 activity has been confirmed by clinical studies (Gurley et al., 2005; Gurley et al., 2008). There are a number of shortcomings of in vitro study methodology directed at BDIs. "
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    ABSTRACT: Ethnopharmacological relevance: Botanical medicines are frequently used in combination with therapeutic drugs, imposing a risk for harmful botanical-drug interactions (BDIs). Among the existing BDI evaluation methods, clinical studies are the most desirable, but due to their expense and protracted time-line for completion, conventional in vitro methodologies remain the most frequently used BDI assessment tools. However, many predictions generated from in vitro studies are inconsistent with clinical findings. Accordingly, the present study aimed to develop a novel ex vivo approach for BDI assessment and expand the safety evaluation methodology in applied ethnopharmacological research. Materials and methods: This approach differs from conventional in vitro methods in that rather than botanical extracts or individual phytochemicals being prepared in artificial buffers, human plasma/serum collected from a limited number of subjects administered botanical supplements was utilized to assess BDIs. To validate the methodology, human plasma/serum samples collected from healthy subjects administered either milk thistle or goldenseal extracts were utilized in incubation studies to determine their potential inhibitory effects on CYP2C9 and CYP3A4/5, respectively. Silybin A and B, two principal milk thistle phytochemicals, and hydrastine and berberine, the purported active constituents in goldenseal, were evaluated in both phosphate buffer and human plasma based in vitro incubation systems. Results: Ex vivo study results were consistent with formal clinical study findings for the effect of milk thistle on the disposition of tolbutamide, a CYP2C9 substrate, and for goldenseal׳s influence on the pharmacokinetics of midazolam, a widely accepted CYP3A4/5 substrate. Compared to conventional in vitro BDI methodologies of assessment, the introduction of human plasma into the in vitro study model changed the observed inhibitory effect of silybin A, silybin B and hydrastine and berberine on CYP2C9 and CYP3A4/5, respectively, results which more closely mirrored those generated in clinical study. Conclusions: Data from conventional buffer-based in vitro studies were less predictive than the ex vivo assessments. Thus, this novel ex vivo approach may be more effective at predicting clinically relevant BDIs than conventional in vitro methods.
    Full-text · Article · Jan 2015 · Journal of Ethnopharmacology
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    • "In vitro and rat studies found Ginkgo have effects on CYP2C9, CYP2D6 and CYP2E1. But the effect of Ginkgo on CYP3A4 was unclear and some in vitro studies did not appear to be clinically relevant [78–80]. Evidence from pharmacological studies in patients and healthy subjects showed no interaction between Ginkgo and warfarin [81, 82]. "
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    ABSTRACT: Increasing and inadvertent use of herbs makes herb-drug interactions a focus of research. Concomitant use of warfarin, a highly efficacious oral anticoagulant, and herbs causes major safety concerns due to the narrow therapeutic window of warfarin. This paper presents an update overview of clinical findings regarding herb-warfarin interaction, highlighting clinical outcomes, severity of documented interactions, and quality of clinical evidence. Among thirty-eight herbs, Cannabis, Chamomile, Cranberry, Garlic, Ginkgo, Grapefruit, Lycium, Red clover, and St. John's wort were evaluated to have major severity interaction with warfarin. Herbs were also classified on account of the likelihood of their supporting evidences for interaction. Four herbs were considered as highly probable to interact with warfarin (level I), three were estimated as probable (level II), and ten and twenty-one were possible (level III) and doubtful (level IV), respectively. The general mechanism of herb-warfarin interaction almost remains unknown, yet several pharmacokinetic and pharmacodynamic factors were estimated to influence the effectiveness of warfarin. Based on limited literature and information reported, we identified corresponding mechanisms of interactions for a small amount of "interacting herbs." In summary, herb-warfarin interaction, especially the clinical effects of herbs on warfarin therapy should be further investigated through multicenter studies with larger sample sizes.
    Full-text · Article · Mar 2014 · Evidence-based Complementary and Alternative Medicine
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    • "To the authors' knowledge, no studies to date have investigated the drug interaction liability of milk thistle using PBPK modeling and simulation. Of the reported in vitro studies that mention HDIs with milk thistle products, the majority urge caution when such products are coadministered with sensitive victim drugs due to unknown interaction liability (Beckmann-Knopp et al., 2000; Venkataramanan et al., 2000; Nguyen et al., 2003; Sridar et al., 2004; Etheridge et al., 2007; Deng et al., 2008; Brantley et al., 2010; Mohamed et al., 2010; Doehmer et al., 2011; Mohamed and Frye, 2011). Other studies (Zuber et al., 2002; Jancová et al., 2007; Doehmer et al., 2008) dismiss interaction liability due to the low plasma concentrations of milk thistle constituents or low inhibitory potency. "
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    ABSTRACT: Supported by a usage history that predates written records and the perception that 'natural' ensures safety, herbal products have been incorporated increasingly into Western health care. Consumers often self-administer these products concomitantly with conventional medications without informing their health care provider(s). Such herb-drug combinations can produce untoward effects when the herbal product perturbs the activity of drug metabolizing enzymes and/or transporters. Despite increasing recognition of these types of herb-drug interactions, a standard system for interaction prediction and evaluation is nonexistent. Consequently, the mechanisms underlying herb-drug interactions remain an understudied area of pharmacotherapy. Evaluation of herbal product interaction liability is challenging due to variability in herbal product composition, uncertainty of the causative constituents, and often scant knowledge of causative constituent pharmacokinetics. These limitations are confounded further by the varying perspectives concerning herbal product regulation. Systematic evaluation of herbal product drug interaction liability, as is routine for new drugs under development, necessitates identifying individual constituents from herbal products and characterizing the interaction potential of such constituents. Integration of this information into in silico models that estimate the pharmacokinetics of individual constituents should facilitate prospective identification of herb-drug interactions. These concepts are highlighted with the exemplar herbal products milk thistle and resveratrol. Implementation of this methodology should help provide definitive information to both consumers and clinicians about the risk of adding herbal products to conventional pharmacotherapeutic regimens.
    Preview · Article · Dec 2013 · Drug metabolism and disposition: the biological fate of chemicals
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