The in vitro Inhibitory Potential of Trade Herbal Products on Human CYP2D6‐Mediated Metabolism and the Influence of Ethanol

Abstract

Abstract:The six commonly used trade herbal products, St. John's wort, common valerian, common sage, Ginkgo biloba , Echinacea purpurea and horse chestnut, and ethanol, were investigated for their in vitro inhibitory potential of cytochrome P450 2D6 (CYP2D6)-mediated metabolism. Herbal components were extracted from commercially available products in a way that ensured the same composition of constituents in the extract as in the original trade products. c-DNA baculovirus expressed CYP2D6 was used with dextromethorphan as substrate. Quinidine was included as a positive control inhibitor. A validated high performance liquid chromatography methodology was used to quantify the formation of dextrorphan (product of dextromethorphan O-demethylation). Ethanol showed a biphasic effect on CYP2D6 metabolism, increasing initially the CYP2D6 activity with 175% of control up to a concentration of 1.1%, where after ethanol linearly inhibited the CYP2D6 activity. All the investigated herbs inhibited CYP2D6 activity to some extent, but only St. John's wort, common sage and common valerian were considered possible candidates for in vivo clinically significant effects. They showed IC 50 values of 0.07 ± 7 × 10 -3 mg/ml, 0.8 ± 0.05 mg/ml and 1.6 ± 0.2 mg/ml, respectively. St. John's wort inhibited CYP2D6-mediated metabolism in an uncompetitive manner, while common valerian and common sage in a non-competitive manner demonstrated interherb differences in inhibition patterns and differences when compared to the more homogenous competitive inhibitor quinidine. Common valerian was the only herb that showed a mechanistic inhibition of CYP2D6 activity and attention should be paid to a possible toxicity of this herb.The use of herbs as alternative and/or complementary therapy in the Western world is on the rise and gaining increasing popularity. As people often take different herbs in combination with prescribed Western medication [1][2][3], there is a potential for both pharmacokinetic and pharmacodynamic herb-drug interactions that can disturb Western drug efficacy and safety. This is shown among others with St. John's wort and cyclosporine, Ginkgo biloba and warfarin, garlic and saquinavir, Allium sativum and chloropropamid, and milk thistle and indinavir [4 -6].As herbal preparations consist of multiple, often unidentified, biological active or inactive constituents, the chance that an interaction for a single drug might be higher towards a complex herbal product than towards another single drug. Furthermore, the combined effect of all constituents together in a herb may be different from the anticipated sum effect evaluated from single isolated constituents. This emphasizes the importance of performing interaction studies with crude herbal extracts as an important supplement to studies on isolated herbal fractions.The cytochrome P450 2D6 (CYP2D6) enzyme is anticipated to be involved in the metabolism of about 25% of all used drugs, including cardiovascular drugs, β -adrenergic blocking agents, tricyclic antidepressants, analgesics a...

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