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DOI: 10.1055/s-0039-3400042
High affinity HERG and low affinity Cav1.2 blockers dehydroevodiamine and hortiamine in decoctions of the TCM drug Evodiae fructus
Publication History
Publication Date:
20 December 2019 (online)
Most herbal drugs used in Traditional Chinese Medicine (TCM) are considered safe based on their use over centuries. However, the major alkaloids dehydroevodiamine (1) and hortiamine (2) in Evodiae fructus (fruits of Evodia rutaecarpa) were recently found to be potent blockers of IKr (rapid delayed rectifier current) with proarrhythmic effects in vitro and in vivo.[1] The herbal drug and Evodia-containing products are freely available via various distribution channels.
For a better assessment of possible risks associated with the use of Evodia, we prepared aqueous decoctions according to TCM procedures from a range of commercially available herbal drug samples. The content in extracted alkaloids was determined by LC-MS. In the decoctions 0.3-5.2 mg of 1 and 0.08-0.39 mg of 2 were found per gram of herbal drug (corresponding to approx. 20% of the alkaloid content in the drugs). Taking into account the dosage recommendations of the Chinese Pharmacopoeia for Evodiae fructus, this would correspond to a daily intake of 0.9-11.7 mg of 1 and 0.11-1.8 mg of 2. The effect of these decoctions on action potentials in stem-cell derived cardiomyocytes was studied. Additionally, the effects on HERG (IC50 of IKr inhibition <1 µM) and Cav1.2 (IC50 of ICa inhibition >50 µM) channels expressed in HEK-293 cells was determined.
In conclusion, decoctions of Evodiae fructus lead to the intake of significant amounts of IKr blocking alkaloids 1 and 2. The comparably low potency inhibition of Cav1.2 suggests a high risk for pro-arrhythmic effects such as Torsade de Pointes.[2]
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References
- 1 Baburin I, Varkevisser R, Schramm A, Saxena P, Beyl S, Szkokan P. etal. Dehydroevodiamine and hortiamine, alkaloids from the traditional Chinese herbal drug Evodia rutaecarpa, are IKr blockers with proarrhythmic effects in vitro and in vivo. Pharmacol Res 2018; 131: 150-163
- 2 Kramer J, Obejero-Paz CA, Myatt G, Kuryshev YA, Bruening-Wright A, Verducci JS, Brown AM. MICE models: superior to the HERG model in predicting Torsade de Pointes. Sci Rep 2013; 3: 2100