Assessing the Clinical Significance of Botanical Supplementation on Human Cytochrome P450 3A Activity: Comparison of a Milk Thistle and Black Cohosh Product to Rifampin and Clarithromycin

University of Arkansas at Little Rock, Little Rock, Arkansas, United States
The Journal of Clinical Pharmacology (Impact Factor: 2.48). 03/2006; 46(2):201-13. DOI: 10.1177/0091270005284854
Source: PubMed


Phytochemical-mediated modulation of cytochrome P450 enzymes (CYPs) may underlie many herb-drug interactions. This study's purpose was to assess the effects of milk thistle and black cohosh supplementation on CYP3A activity and compare them to a clinically recognized inducer, rifampin, and inhibitor, clarithromycin. Healthy volunteers were randomly assigned to receive a standardized milk thistle (900 mg) or black cohosh (80 mg) supplement for 14 days. Subjects also received rifampin (600 mg) and clarithromycin (1000 mg) for 7 days as positive controls for CYP3A induction and inhibition, respectively. Midazolam was administered orally before and after each supplementation and control period. The effects of milk thistle, black cohosh, rifampin, and clarithromycin on midazolam pharmacokinetics were determined using noncompartmental techniques. Unlike those observed for rifampin and clarithromycin, midazolam pharmacokinetics was unaffected by milk thistle or black cohosh. Milk thistle and black cohosh appear to have no clinically relevant effect on CYP3A activity in vivo.

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Available from: Bill Gurley, Sep 24, 2014
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    • "In a human interaction study, CR (80 mg) was given over 14 days to 19 healthy subjects . No clinically relevant interaction with CYP3A4 could be demonstrated using midazolam as the test drug (Gurley et al. 2006a). In MDA-MB-453 and MCF-7 human breast cancer cells, CYP1A1, CYP1B1 (Einbond et al. 2007; Gaube et al. 2007) and ABCC3 (MRP3) (Einbond et al. 2007) were up-regulated. "
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    ABSTRACT: The cardinal climacteric symptoms of hot flushes and night sweats affect 24-93% of all women during the physiological transition from reproductive to post-reproductive life. Though efficacious, hormonal therapy and partial oestrogenic compounds are linked to a significant increase in breast cancer. Non-hormonal treatments are thus greatly appreciated. This systematic review of published hormonal and non-hormonal treatments for climacteric, and breast and prostate cancer-associated hot flushes, examines clinical efficacy and therapy-related cancer risk modulation. A PubMed search included literature up to June 19, 2014 without limits for initial dates or language, with the search terms, (hot flush* OR hot flash*) AND (clinical trial* OR clinical stud*) AND (randomi* OR observational) NOT review). Retrieved references identified further papers. The focus was on hot flushes; other symptoms (night sweats, irritability, etc.) were not specifically screened. Included were some 610 clinical studies where a measured effect of the intervention, intensity and severity were documented, and where patients received treatment of pharmaceutical quality. Only 147 of these references described studies with alternative non-hormonal treatments in post-menopausal women and in breast and prostate cancer survivors; these results are presented in Additional file 1. The most effective hot flush treatment is oestrogenic hormones, or a combination of oestrogen and progestins, though benefits are partially outweighed by a significantly increased risk for breast cancer development. This review illustrates that certain non-hormonal treatments, including selective serotonin reuptake inhibitors, gabapentin/pregabalin, and Cimicifuga racemosa extracts, show a positive risk-benefit ratio.
    Full-text · Article · Dec 2015 · SpringerPlus
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    • "In the case of valerian (Table 1), preclinical data predicting drug–botanical dietaryBilberry (Vaccinium myrtillus) OATP2B1 (Mao et al., 2013Stout and Cimino, 2014) — — — Dandelion (Taraxacum spp.) CYP1A2 (Maliakal and Wanwimolruk, 2001) UDPGT (Zhou et al., 2004) — — — Dong quai (Angelica sinensis) a,b CYP1A (Lin et al., 1998); CYP3A4 (Guo et al., 2001) CYP2D6 (Tang et al., 2006); CYP3A4 (Gurley et al., 2006)— — — Evening primrose oil (Oenothera biennis) a Cis-linoleic acid: CYP1A2 (Zou et al., 2002); CYP2C9, CYP2C19, CYP2D6, CYP3A4 (Netsch et al., 2006Yuan et al., 2014); CYP2C8, CYP2C9, CYP2C19 (Whitten et al., 2006)— — — — Licorice root (Glycyrrhiza glabra, G. uralensis, and G. inflate) a CYP2A1 (Paolini et al., 1999); CYP2B6, CYP2C8, CYP2C9, CYP2C19 (Johne et al., 1999;Lefebvre et al., 2004); CYP3A4 (Johne et al., 1999;Gorski et al., 2004;Lefebvre et al., 2004); UGT1A1 (Guo et al., 2013) CYP1A2 (Kent et al., 2002); CYP2B6 (Lefebvre et al., 2004)— — — Plant sterols (e.g., sitosterol) MDR1 (Nabekura et al., 2008); MRP1 (Chow et al., 2006 "
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    ABSTRACT: The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but under-investigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport and/or metabolism of pharmaceutical agents. Clinical trials of drug-botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical studies. For example, Phase I clinical trials have confirmed preclinical studies and clinical case reports that St. John's wort (Hypericum perforatum) induces cytochrome P450 3A4/5. However, clinical studies of most botanicals that were predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and/or CYP3A4. Here, we highlight discrepancies between preclinical and clinical data concerning drug-botanical interactions and critically evaluate why some preclinical models perform better than others in predicting the potential for drug-botanical interactions. Gaps in our knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport and metabolism.
    Preview · Article · Jun 2015 · Planta Medica
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    • "Moreover, it has been shown by an in vitro study that certain triterpene glycosides isolated from black cohosh only weakly inhibited human CYP3A4 (Tsukamoto et al., 2005). This is in agreement with in vivo data suggesting no clinically significant interactions between black cohosh and CYP3A4 (Gurley et al., 2005Gurley et al., , 2006). Because hot flashes are the main indication for black cohosh use, women who experience this side effect of tamoxifen may decide to use black cohosh as a presumably safe remedy. "
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    ABSTRACT: Export Date: 18 October 2014
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