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
ABSTRACT 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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ABSTRACT: 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.Journal of Ethnopharmacology 01/2015; 163. DOI:10.1016/j.jep.2015.01.021 · 2.94 Impact Factor
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ABSTRACT: Abstract Ginkgo biloba leaf extracts (GLEs) are popular herbal remedies for the treatment of Alzheimer's dementia, tinnitus, vertigo and peripheral arterial disease. As GLEs are taken regularly by older people who are likely to also use multiple other drugs for the treatment of, e.g. hypertension, diabetes, rheumatism or heart failure, potential herb-drug interactions are of interest. Preclinical studies of high doses/concentrations of GLEs of varying quality and standardization hinted at both an inhibition and induction of metabolic enzymes and transporters. However, in humans, positive in vitro-findings could not be replicated in vivo. At maximum recommended doses of 240 mg/day, a clinically relevant interaction potential of the standardized GLE EGb 761 could not be shown. GLE doses higher than the recommended ones led to a weak induction of the CYP2C19-mediated omeprazole 5-hydroxylation, and a weak inhibition of the CYP3A4-mediated midazolam 1'-hydroxylation, respectively. Also, the regular intake of a poorly characterized GLE at a dose of 360 mg/day slightly increased the bioavailability of talinolol, a substrate of P-glycoprotein and various organic anion-transporting polypeptides. Thus, regarding pharmacokinetic herb-drug interactions, the intake of the standardized GLE, EGb 761, together with synthetic drugs appears to be safe as long as daily doses up to 240 mg are consumed. If this applies to other extracts prepared according to the European Pharmacopoeia remains uncertain. Also, a relevant potential for drug interactions cannot be excluded for poorly standardized GLEs used in many food supplements.Drug Metabolism Reviews 08/2013; 45(3):353-85. DOI:10.3109/03602532.2013.815200 · 6.29 Impact Factor
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ABSTRACT: Berberine is an isoquinoline alkaloid isolated from the root and bark of plants such as goldenseal, Berberis, and Chinese goldthread. Berberine-containing crude drugs have been used as an antimicrobial remedy against gastrointestinal infections for thousands of years. It is also widely used in Asian countries for diabetes, hypertension, and hypercholesterolemia therapy. Potential drug-drug interactions are of concern because of the wide usage of berberine. A few studies have reported interactions between berberine and cytochromes P450 (CYPs) in vitro, but little is known about whether berberine influences CYPs in vivo, especially after repeated administration. In this study, eight-week-old male C57BL/6 mice were given berberine orally (0, 10, 30, 100, 300 mg/kg, i.g., daily for 14 days), and the effect of berberine on over 20 major Cyps and related nuclear receptors in mice livers were examined at both the mRNA and enzyme activity levels. In general, liver function of mice treated with various doses of berberine had no significant change, and repeated oral administration of the 3 lower doses of berberine for 14 days did not affect the expression of genes examined. However, after the highest dose of berberine (300mg/kg), Cyp3a11 and Cyp3a25 mRNA decreased 67.6 and 87.4%, respectively, whereas Cyp1a2 mRNA increased 43.2%, and enzyme activities of Cyp3a11 and Cyp2d22 decreased 67.9 and 32.4%, respectively. Cyp2a4, 2b10 and Cyp2c29 were not altered at both mRNA and enzyme activity levels. If studies in mice extrapolate to humans, lower doses of berberine appear to present a low risk of producing drug-drug interactions as a result of changed Cyp enzyme activity. However, high doses of berberine may suppress Cyp activities and result in drug-drug interactions.Journal of ethnopharmacology 09/2011; 138(1):111-8. DOI:10.1016/j.jep.2011.08.058 · 2.94 Impact Factor