EGCG and drug interactions -
Subjects were asked to report any adverse effects at each visit to the study center. This was an open-label, three-phase randomized crossover study. Subjects were given a single dose of rosuvastatin 10 mg Crestor ® , Astra Zeneca on 3 occasions: 1. with soy isoflavones extract. The green tea extract and soy isoflavones extract were given at a dose thought to contain EGCG mg once daily or isoflavones 80 mg once daily for 14 days before rosuvastatin dosing with at least a 4-week washout period between phases.
The herbal extracts were present as a powder which was taken in ml water at room temperature. Blood samples were taken at intervals from 0 to 24 h on the rosuvastatin dosing days. During the study, subjects were frequently reminded of the requirements for diet restrictions, and they were requested to record their daily food intake, including the main meals, snacks and beverages of the day by using a simple food diary, which can help to monitor the food compliance during the study.
Green tea extract and soy isoflavones extract products were manufactured by the Hong Kong Institute of Biotechnology HKIB in accordance with Good Manufacturing Practice GMP.
Standard heavy metal, microbial and pesticides tests were performed to ensure the products fulfilled the safety requirement set out by the Department of Health in Hong Kong. Each green tea extract sachet claimed to contain mg standardized EGCG.
Each soy extract sachet claimed to contain 80 mg standardized total isoflavones. The plasma samples were prepared using liquid—liquid extraction with diethyl ether.
Chromatographic separation was accomplished on an Xterra MS C18 column 50 × 2. The mobile phase consisted of a gradient mixture of 0. The gradient was then returned to the initial mobile phase concentration in a chromatographic run of 8 min. The lower limit of quantification of rosuvastatin was 0.
The linear range of the method was from 0. DNA was extracted from the blood samples using High Pure PCR Template Preparation Kits Roche Applied Science.
The pharmacokinetic parameters of rosuvastatin were calculated using non-compartmental methods with the aid of the computer program WinNolin version 2.
The maximum plasma concentration C max and time to C max t max were obtained directly from the observed concentration-time data. The primary outcome was the difference in rosuvastatin pharmacokinetic parameters with and without herb consumptions.
Logarithmic transformation was used for pharmacokinetic variables, except for t max. The pharmacokinetic parameters of rosuvastatin after consumption of green tea or soy isoflavones were compared with those when the drugs were taken without these herbs by repeated measures ANOVA, except for t max values for which the Friedman rank test was used.
The comparisons of the pharmacokinetic parameters and interactions among genotype groups were determined using ANOVA for normally distributed data or the Kruskal-Wallis test for skewed data.
In a previous study, a herb-drug interaction between baicalin and rosuvastatin was related to different SLCO1B1 haplotype groups in 18 healthy Chinese subjects, with 6 in each haplotype group.
A similar sample size of 20 subjects was used in the current study to explore the potential herb-drug interactions and their relationship with the ABCG2 transporter polymorphism. The green tea extract product mainly contained — -epigallocatechingallate EGCG as it corresponded with the EGCG standard on the chromatogram, although the other 6 chemical markers were also present in small amounts.
The amount of EGCG within each sachet daily dose was The EGCG may have undergone some epimerization to gallocatechin gallate GCG during the extraction process which involved some heating and there was a small peak on the chromatogram close to the EGCG peak which was not identified or quantified, but may have been GCG.
The soy isoflavone product contained all 7 chemical markers, namely glycitin, daidzin, genistin, daidzein, glycitein, genistein and acetylgenistin in amounts of There were some other small unidentified peaks on the chromatogram which may represent other components of the extract that contribute to the total isoflavones.
In the 20 healthy Chinese male volunteers [mean ±SD age: Reduction in systemic exposure to rosuvastatin with EGCG was observed in 17 out of 20 subjects. Table 1. Demographics of the 20 study subjects in the rosuvastatin-herb interaction study.
Figure 1. Effects of green tea extract and soy isoflavones on the pharmacokinetics of rosuvastatin in 20 healthy subjects. Data are arithmetic mean ±SD. Table 2. Effect of green tea extract and soy isoflavones on the pharmacokinetic parameters of rosuvastatin in 20 healthy subjects.
The soy isoflavones had no significant effect on the pharmacokinetics of rosuvastatin Figure 1 ; Table 2. Figure 2.
Data are arithmetic mean. A , Baseline; B , After green tea extract; C , After soy isoflavones. Figure 3. The subjects did not report any adverse events during the periods of repeated intake of green tea extract or soy isoflavones or the single doses of rosuvastatin. Beverages and food can interact with various medications and may alter their pharmacokinetic properties.
In this study, we tested the hypothesis whether green tea or soy isoflavones would influence the pharmacokinetics of rosuvastatin, a commonly used statin, in Hong Kong Chinese subjects and whether genetic polymorphisms in drug transporters and drug metabolizing enzymes would affect the interactions.
The soy isoflavones had no significant effect on any of the pharmacokinetic parameters of rosuvastatin. Green tea or EGCG has also been reported to improve many cardiovascular risk factors, including plasma lipids, blood pressure, inflammatory biomarkers, oxidative stress, glucose and insulin resistance 31 — The mechanisms by which green tea exerts its purported cardiovascular protective effects are subjects of interest in the field.
Green tea catechin-enriched extracts are available over the counter as dietary supplements like vitamins and weight reduction pills and are widely and increasingly used by the general public, especially in those with increased cardiovascular risk, such as with hypercholesterolaemia.
However, in vitro and in vivo studies suggested that green tea polyphenols may affect the absorption and metabolism of drugs by affecting the expression or activities of drug-metabolizing enzymes and drug transporters It has been shown that green tea catechins inhibit the activities of CYP1A1, 1A2, 2A6, 2C9, 2E1, and 3A4 and may also induce the expression of CYP1A1, 1A2, 2D6, 2E1, 3A4 in cell lines 35 , Several studies have also indicated the inhibition of ABCB1 and ABCG2 activity by EGCG Roth et al.
showed that EGCG inhibited OATP1A2- and OATP2B1-mediated uptake of estronesulfate in a concentration-dependent manner in cells expressing these transporters On the other hand, EGCG was shown to activate OATP1B3 in in vitro studies Various compounds can induce transporters such as P-gp and possibly hepatic OATP1B transporters by activating the pregnane X receptor PXR The herbal medicine baicalin was shown to reduce the plasma concentrations of rosuvastatin in an OATP1B1 haplotype—dependent manner, suggesting the effect was mediated by induction of hepatic rosuvastatin uptake through OATP1B1 However, after giving the EGCG daily for 10 days, the systemic exposure of rosuvastatin was not significantly different from the baseline value before EGCG, although the AUC and C max values were intermediate between the values before and after a single dose of EGCG The effect of the single dose was thought to be due to inhibition of intestinal uptake transporters OATP2B1 or OATP1A2, considering that the predicted plasma concentration would be sufficient to inhibit OATP2B1 The authors speculated that long-term treatment might result in accumulation sufficient to inhibit liver uptake by OATP1B1 or to upregulation of enterocyte transporters.
In addition to EGCG, other gallated catechins in green tea, such as ECG, can inhibit OATP1A2, OATP1B1, and OATP2B1 Therefore, green tea may have a different effect from pure EGCG.
Rosuvastatin undergoes little metabolism, but it is a substrate of multiple transporters, including OATPs and ABCG2 Similarly, inhibition of ABCG2 by green tea might also be predicted to result in increased plasma concentration of rosuvastatin.
However, in this study in healthy volunteers, treatment with green tea extract containing mainly EGCG was associated with reduced systemic exposure to rosuvastatin.
This may be explained by an inhibitory effect of EGCG on the intestinal uptake transporters OATP2B1 or OATP1A2, like the single-dose study of Kim et al. A study using cultured cells transfected with human P-gp or human BCRP showed no significant effect of green tea components EC, ECG, EGC, or EGCG on P-gp-mediated or BCRP-mediated dasatinib efflux, whereas some fruit juice components had a strong inhibitory effect Lack of effect of the ABCG2 polymorphism on the effect of green tea extract on rosuvastatin pharmacokinetic in the present study would also suggest that the effect is not medicated by ABCG2 induction.
Green tea was shown to significantly decrease the C max and AUC of nadolol by In vitro experiments revealed that nadolol is a substrate of OATP1A2 and green tea significantly inhibited OATP1A2-mediated nadolol uptake. Further studies are needed to investigate the mechanisms underlying the interaction between rosuvastatin and EGCG.
The most likely mechanisms appear to be inhibition of intestinal uptake by OAPT1A2 or activation of liver uptake by induction of OATP1B3 or OATP1B1. The former might be expected to reduce the lipid lowering effect of rosuvastatin whereas the latter might increase it.
This study has several limitations that need to be considered. Firstly, this study only assessed one dosage for each herb product e. It is known that interactions between herbs and drugs may be dose-dependent.
Evaluating a higher dose or a lower dose may help to provide a better understanding of the interaction between statins and green tea or soy isoflavones. Secondly, it has been shown that taking EGCG 8 or 4 h before sunitinib administration had no effect on the pharmacokinetics of sunitinib in rats, whereas taking the two together reduced the bioavailability of sunitinib probably because of a physical reaction between the two compounds 49 , suggesting separation of dosing of green tea and drugs may reduce any herb-drug interaction.
To maximize the possibility of finding an interaction between statins and green tea, subjects were taking green tea extract and statins simultaneously on the dosing day, so that a physical interaction between the two substances cannot be excluded.
It would be useful to assess whether the separation of dosing has different effects. During the study, we instructed the study participants to take the study product on an empty stomach at least 1 h before breakfast after overnight fasting to enhance the bioavailability of EGCG and to reduce the variations in EGCG bioavailability caused by food.
They were requested not to take alcohol, tea, grapefruit juice, caffeine, soybean milk or dietary supplements and herbal products 2 weeks before and throughout the study. Subjects were educated about the importance of their compliance to the herbs and dietary restrictions for this research at the beginning of the study and they were reminded frequently of these requirements.
The compliance to instructions on EGCG and soy isoflavones intake or dietary restrictions was monitored by using a food diary. This approach inevitably relied on the subjects' cooperation and honesty and may not be objective, but it was a practical way to conduct the study.
It would be important to further evaluate the mechanisms responsible for the observed interactions and to assess whether these pharmacokinetic interactions have any impact on the lipid-lowering effect of statins in patients requiring long-term statin therapy. There was no significant effect of soy isoflavones on rosuvastatin pharmacokinetics.
Further studies should be performed to investigate the underlying mechanisms responsible for this observed interaction and to assess the clinical relevance in patients receiving long-term statins.
The studies involving human participants were reviewed and approved by the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee with reference number CRE Written informed consent was obtained from the individual s for the publication of any potentially identifiable images or data included in this article.
WZ and MH analyzed the data and wrote this manuscript. BT designed the research project. HL, EW, CL, CW, and CH performed the experiments. BT and CH revised this manuscript. All authors contributed to the article and approved the submitted version. This study was supported by the Health and Health Services Research Fund of the Food and Health Bureau, Hong Kong Special Administrative Region Government The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. GT is containing polyphenols that interfere with many drugs.
The most important of these polyphenol compounds is epigallocatechingallate EGCG , which most of the reported interactions are due to the presence of EGCG.
Interaction of GT with different drugs occurs in the context of both pharmacodynamics and pharmacokinetics that includes drug absorption, metabolism, and renal excretion.
The mechanisms of these interactions consist of increase in the concentration included several medications such as melatonin, midazolam, and amlodipine consuming after GT; these interactions can be toxic. Additionally, it has been reported that serum levels of several drugs such as nadolol, digoxin, amoxicillin, and clozapine are decreased and their efficacy are reduced when they simultaneously administer with GT.
The serum concentration of rhodamin , quinidine, and doxorubicin have increased when these drugs were co-administered with GT. GT is containing polyphenols that interfere with many drugs. The most important of these polyphenol compounds is epigallocatechingallate EGCG , which most of the reported interactions are due to the presence of EGCG.
Interaction of GT with different drugs occurs in the context of both pharmacodynamics and pharmacokinetics that includes drug absorption, metabolism, and renal excretion.
The mechanisms of these interactions consist of increase in the concentration included several medications such as melatonin, midazolam, and amlodipine consuming after GT; these interactions can be toxic.
Additionally, it has been reported that serum levels of several drugs such as nadolol, digoxin, amoxicillin, and clozapine are decreased and their efficacy are reduced when they simultaneously administer with GT. The serum concentration of rhodamin , quinidine, and doxorubicin have increased when these drugs were co-administered with GT.
GT has pharmacodynamics interactions with a few drugs such as a hydrochlorothiazide. As proposed and discussed here, GT has the potential for interactions with numerous other drugs and thus clinicians should be aware of reported and potential interaction of GT with various medications in order to avoid adverse reactions and achieve expected clinical response.
pISSN: eISSN: Skip to main content Skip to main navigation menu Skip to site footer. Review Article. School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Abstract Green tea GT is among the most common drinks in the world.
About this article How to cite References 1. P Werba J, Misaka S, G Giroli M, et al. Overview of green tea interaction with cardiovascular drugs. Curr Pharm Des ;21 9 Kim T-e, Ha N, Kim Y, et al. Effect of epigallocatechingallate, major ingredient of green tea, on the pharmacokinetics of rosuvastatin in healthy volunteers.
Drug Des Devel Ther ; Han X, Zhang H, Hao H, Li H, Guo X, Zhang D. Effect Of epigallocatechingallate on the pharmacokinetics of amlodipine in rats. Xenobiotica ;49 8 Asher GN, Corbett AH, Hawke RL. Common herbal dietary supplement—drug interactions.
Am Fam Physician ;96 2 Cascorbi I. Drug interactions—principles, examples and clinical consequences. Dtsch Arztebl Int ; Chakraborty M, Kamath JV. Pharmacodynamic interaction of green tea extract with hydrochlorothiazide against ischemia-reperfusion injury-induced myocardial infarction.
J Adv Pharm Technol Res ;5 3 Ali B, MS Jamal Q, Shams S, et al. CNS Neurol Disord Drug Targets ;15 5 Shehab NG, Khan RKG, Elgailani ESE, Shawish KYA. Tropical Journal of Pharmaceutical Research ;17 10 Zhao YH, Abraham MH, Le J, et al.
Rate-limited steps of human oral absorption and QSAR studies. Pharm Res ;19 10 Schanker L. Mechanisms of drug absorption and distribution. Annual Review of Pharmacology ;1 1 Kiss T, Timár Z, Szabó A, et al.
Effect of green tea on the gastrointestinal absorption of amoxicillin in rats.
Green Enhance feeling of fullness Interactionss is among the EGCG and drug interactions common drinks in the world. Erug are some reports on interactions between GT and some intfractions. This paper attempts to provide a comprehensive review of this subject. The data are collected by searching PubMed, Scopus, Web of science, and Embase. The keywords used as search terms are "camellia sinensis", "pharmacodynamics", "pharmacokinetic", "EGCG", and "drug interaction". We have found 24 eligible articles.
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