Noncompetitive inhibition of human <scp>CYP</scp>2C9 in vitro by a commercial <i>Rhodiola rosea</i> product

Thu, Ole Kristian Forstrønen; Spigset, Olav; Hellum, Bent H.

doi:10.1002/prp2.324

Cited by 9 publications

(9 citation statements)

References 29 publications

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“…The positive control reversible inhibitors all reduced their respective P450 enzyme activity ( Fig. 3; Table 8) in a manner consistent with the literature (Ring et al, 1996;Suzuki et al, 2002;Emoto et al, 2003;Walsky et al, 2006;VandenBrink et al, 2011;Zhao et al, 2012;Thu et al, 2017). CAW-R61J was found to be a relatively weak reversible inhibitor for most of the P450s tested.…”

Section: Resultssupporting

confidence: 84%

Centella asiaticaWater Extract Shows Low Potential for Cytochrome P450–Mediated Drug Interactions

Wright

Magaña

Laethem³

et al. 2020

Drug Metab Dispos

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Centella asiatica (CA) shows considerable promise for development as a botanical drug for cognitive decline. Its primary bioactive components include triterpene glycosides asiaticoside and madecassoside and their corresponding aglycones asiatic acid and madecassic acid. Exploration of the bioactivity of CA's caffeoylquinic acids is ongoing. In this study, an aqueous extract of CA (CAW-R61J) was evaluated for drug interaction potential through inhibition or induction of P450 enzymes, as required by the US Food and Drug Administration. CAW-R61J was assessed for induction potential of CYP1A2, CYP2B6, and CYP3A4 using transporter-certified cryopreserved human hepatocytes in sandwich culture. Gene expression of these target P450s was quantified, and enzyme activities were determined to confirm gene expression results. No induction was observed up to 16.7 mg/ml CAW-R61J (equivalent to 1.1 mM asiaticoside, 0.8 mM madecassoside, 0.09 mM asiatic acid, and 0.12 mM madecassic acid). Reversible and time-dependent inhibitory effects of CAW-R61J on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 were evaluated using human liver microsomes. CAW-R61J showed weak reversible inhibition of most of the P450 forms tested, with the strongest being CYP2C9 (IC 50 of 330 mg/ml). CAW-R61J (£1000 mg/ml) was not a time-dependent inhibitor of any of these P450 enzymes. In summary, CAW-R61J had no, or only a weak impact, on P450 induction and inhibition in vitro. The clinical relevance of these results will depend on the in vivo concentration of CAW-R61J components achieved in humans. Plasma triterpene concentrations measured in our recent clinical studies suggest minimal risk of P450-mediated drug interactions by these components. SIGNIFICANCE STATEMENT A preparation of Centella asiatica is currently under clinical development for the prevention or treatment of cognitive decline. The US Food and Drug Administration required an evaluation of its potential for drug interactions mediated through drug-metabolizing enzymes. This in vitro study revealed minimal induction or inhibition of a range of P450 enzymes, including CYP3A4, by the C. asiatica extract, suggesting a low potential for drug interactions modulated by P450 metabolism.

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Section: Resultssupporting

confidence: 84%

Centella asiaticaWater Extract Shows Low Potential for Cytochrome P450–Mediated Drug Interactions

Wright

Magaña

Laethem³

et al. 2020

Drug Metab Dispos

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“…The results of herb–drug interaction studies of various adaptogens are contradictory 1–4,598,626–628 . Interactions with some CYP isoenzymes have been observed in vitro studies only in high concentrations of herbal extracts that are far beyond their blood levels when taken in the standard therapeutic doses and not associated with active markers 1,598,626–628 .…”

Section: Challenges and Regulatory Issuesmentioning

confidence: 99%

Evolution of the adaptogenic concept from traditional use to medical systems: Pharmacology of stress‐ and aging‐related diseases

Panossian¹,

Efferth

Shikov

et al. 2020

Medicinal Research Reviews

196

124

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Adaptogens comprise a category of herbal medicinal and nutritional products promoting adaptability, resilience, and survival of living organisms in stress. The aim of this review was to summarize the growing knowledge about common adaptogenic plants used in various traditional medical systems (TMS) and conventional medicine and to provide a modern rationale for their use in the treatment of stress‐induced and aging‐related disorders. Adaptogens have pharmacologically pleiotropic effects on the neuroendocrine‐immune system, which explain their traditional use for the treatment of a wide range of conditions. They exhibit a biphasic dose‐effect response: at low doses they function as mild stress‐mimetics, which activate the adaptive stress‐response signaling pathways to cope with severe stress. That is in line with their traditional use for preventing premature aging and to maintain good health and vitality. However, the potential of adaptogens remains poorly explored. Treatment of stress and aging‐related diseases require novel approaches. Some combinations of adaptogenic plants provide unique effects due to their synergistic interactions in organisms not obtainable by any ingredient independently. Further progress in this field needs to focus on discovering new combinations of adaptogens based on traditional medical concepts. Robust and rigorous approaches including network pharmacology and systems pharmacology could help in analyzing potential synergistic effects and, more broadly, future uses of adaptogens. In conclusion, the evolution of the adaptogenic concept has led back to basics of TMS and a new level of understanding of holistic approach. It provides a rationale for their use in stress‐induced and aging‐related diseases.

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“…It was suggested that these phenolic compounds (rosavin, rosarin, rosin, salidroside/rhodioloside, and tyrosol) have no impact on activity of CYP450 enzymes and do not inhibit CYP3A4, CYP2D6, or CYP1A2 ( Hellum et al, 2010 ; Xu et al, 2013 ; Thu et al, 2016a ). The presence of minor amounts of herbacetin rhamnosides (rhodiosin and rhodionin) may presumably induce inhibition of CYP2D6 ( Xu et al, 2013 ) in some commercial preparations of Rhodiola ( Thu et al, 2016b , 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Assessing the Quality and Potential Efficacy of Commercial Extracts of Rhodiola rosea L. by Analyzing the Salidroside and Rosavin Content and the Electrophysiological Activity in Hippocampal Long-Term Potentiation, a Synaptic Model of Memory

Dimpfel

Schombert²,

Panossian³

2018

Front. Pharmacol.

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Rhodiola rosea L. roots and rhizome extracts are active ingredients in adaptogenic herbal medicinal products (HMP) and dietary supplements for temporary relief of symptoms of stress, such as fatigue and weakness. R. rosea extract has a stimulating effect on the CNS, suggesting potential benefits on cognitive functions, memory, learning, and attention. The reproducible efficacy and quality of preparations of the underground parts of R. rosea depend on the highly variable content of the active markers, salidroside and rosavin, which affect the quality of HMP and dietary supplements. However, it is not clear which analytical markers are important for assessing the efficacy of R. rosea preparations intended for use in aging-induced mild cognitive disorders, such as attenuated memory, attention, and learning. Furthermore, the activity of various commercial R. rosea extracts has not been correlated with their content. Here, the biological activities of salidroside, rosavin, and seven commercial extracts of underground parts of R. rosea were assessed using a synaptic model of memory: long-term potentiation (LTP) of synaptic transmission in hippocampus slices. A high degree of variation in the content of all active markers was observed. One extract from China lacked rosavin, and there was even variation in the extracts from the Altai geographic region. In vitro, rosavin, salidroside and all tested R. rosea extracts potentiated electric stimulation of an intra-hippocampal electric circuit, which resulted in higher responses of the pyramidal cells in isolated hippocampus slices. Rosavin was more active at higher concentrations than salidroside; while, salidroside was more effective at lower concentrations. The highest content of both active markers was found in the extracts that were active at the lowest concentrations tested; while, some extracts contained some other compounds that presumably reduced the efficacy due to antagonistic interactions. Standardized content of active markers is necessary for the quality control of herbal preparations containing R. rosea extracts, but insufficient for assessment of their potential efficacy. Additional bioassays are needed to assure the reproducible pharmacological activity of R. rosea extracts; therefore, the LTP of synaptic transmission in hippocampus slices may serve as a validation tool for the quality control of R. rosea extracts.

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Noncompetitive inhibition of human CYP2C9 in vitro by a commercial Rhodiola rosea product

Cited by 9 publications

References 29 publications

Centella asiaticaWater Extract Shows Low Potential for Cytochrome P450–Mediated Drug Interactions

Centella asiaticaWater Extract Shows Low Potential for Cytochrome P450–Mediated Drug Interactions

Evolution of the adaptogenic concept from traditional use to medical systems: Pharmacology of stress‐ and aging‐related diseases

Assessing the Quality and Potential Efficacy of Commercial Extracts of Rhodiola rosea L. by Analyzing the Salidroside and Rosavin Content and the Electrophysiological Activity in Hippocampal Long-Term Potentiation, a Synaptic Model of Memory

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