The enhancement of cardiotoxicity that results from inhibiton of CYP 3A4 activity and hERG channel by berberine in combination with statins

Feng, Pan-Feng; Zhao, Lei; Guo, Feng-Feng; Zhang, Bo; Li, Fang; Zhan, Ge; Xu, Xue-Qi; Fang, Qingwei; Liang, Zhaoguang; Li, Baoxin

doi:10.1016/j.cbi.2018.07.022

Cited by 28 publications

(23 citation statements)

References 28 publications

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“…ddi was detected following the combined use of P2Y12 inhibitors and statins, however, no bleeding was observed in the internal organs or skin of the rats. according to a previous report, simvastatin can reduce potassium voltage-gated channel subfamily H member 2 current by accelerating channel inactivation, and can increase the risk of long QT syndrome (lQTS) with long-term use (35). The combination of ticagrelor with simvastatin may lead to an increase in the plasma concentration of simvastatin by inhibiting cYP3a4 activity, which may in turn contribute to the higher risk of drug induced lQTS and torsade de pointes.…”

Section: Treatment Group --------------------------------------------mentioning

confidence: 98%

Evaluation of cytochrome P450 3A4‑mediated drug‑drug interaction potential between P2Y12 inhibitors and statins

et al. 2019

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Ticagrelor and prasugrel are widely used in the treatment of acute coronary syndrome. The co-administration of ticagrelor or prasugrel with statins in the clinic has already drawn a great deal of attention. The aims of the present study were to evaluate the safety and effectiveness, and guide the rational clinical use of, co-administration of ticagrelor or prasugrel with statins by exploring potential drug interactions. The activity of cytochrome P450 family 3 subfamily a member 4 (cYP3a4) was detected, and its protein and mrna expression levels were measured in a rat model and liver microsomes to evaluate the effect of the drug combinations on cYP3a4. High performance liquid chromatography, western blotting and reverse transcription-quantitative Pcr were used to perform these investigations. The in vitro experiments suggested that ticagrelor inhibited cYP3a4 activity, with ic 50 and inhibitor constant (K i) values of 68.74 and 26.47 µM, respectively; prasugrel also inhibited cYP3a4, activity with ic 50 and K i values of 16.24 and 10.84 µM, respectively. When different dosages of the antagonists were combined with simvastatin or atorvastatin, the metabolic rate was reduced more effectively at higher dosages when compared with lower dosages. an in vivo pharmacokinetic study demonstrated that the co-administration of ticagrelor or prasugrel with simvastatin caused an increase in the principal pharmacokinetic parameters of the probe drug dapsone [area under the concentration/time curve (auc) 0-t , auc 0-∞ and t 1/2 ] and a decrease in clearance compared with ticagrelor, prasugrel or simvastatin alone. Additional studies confirmed that the two investigated P2Y12 inhibitors were able to decrease the protein level of cYP3a4 by promoting protein degradation through the proteasomal pathway, and combination with statins such as simvastatin had a synergistic inhibitory effect on cYP3a4 activity. These results demonstrated that the co-administration of P2Y12 inhibitors with simvastatin could markedly inhibit the activity of CYP3A4, and these findings will further influence the assessment of the clinical effectiveness (reduced or enhanced efficacy) and safety (bleeding and rhabdomyolysis) in the clinic.

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Section: Treatment Group --------------------------------------------mentioning

confidence: 98%

Evaluation of cytochrome P450 3A4‑mediated drug‑drug interaction potential between P2Y12 inhibitors and statins

et al. 2019

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“…P450 (CYP) 3A is the highest expression subfamily, including isoforms CYP3A4, CYP3A5, CYP3A7, and CYP3A43 (Eichelbaum and Burk 2001). CYP3A4 is the isoforms expressed in the liver and intestine (Eichelbaum and Burk 2001), which can oxidize a variety of drugs through many metabolic processes for detoxification (Dresser et al 2000), and it is responsible for about 60% of the metabolism of currently known drugs (Feng et al 2018, Zhou et al 2005. Clinically important CYP3A4 inhibitors include antifungals (e.g.…”

Section: Other Mechanismsmentioning

confidence: 99%

“…ritonavir and delavirdine) (Dresser et al2000, Zhou et al 2005. These inhibitors can boost the plasma concentration of itself or other drugs that directly act on hERG and enhance cardiotoxicity (Feng et al 2018, Zhi et al 2015. In the list, ritonavir in lopinavir/ritonavir which has been shown to be effective for the treatment of COVID-19 as a strong CYP3A4 inhibitor can increase the oral bioavailability of certain HIV protease inhibitors, such as lopinavir (Dresser et al 2000).…”

Section: Other Mechanismsmentioning

confidence: 99%

Potential therapeutic drugs for COVID-19 risk prolonging QT interval targeting hERG channel

Zhao

Dingding³

et al. 2020

Preprint

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The COVID-19 caused by SARS-CoV-2 poses a huge challenge to the medical system, especially the safe and effective COVID-19 treatment methods, forcing people to look for drugs that may have therapeutic effects as soon as possible. Some old drugs have shown clinical benefits after a few small clinical trials attracting great attention. Clinically, however, many drugs including those currently shown to be effective against COVID-19 such as chloroquine, hydroxychloroquine, azithromycin and lopinavir/ritonavir may cause cardiotoxicity through acting on cardiac potassium channel, hERG channel due to their off-target effect. Blocking of hERG prolongs QT intervals on the electrocardiogram and thus might induce severe ventricular arrhythmias and even sudden cardiac death. Therefore, while focusing on the efficacy of COVID-19 drugs, the fact that they block hERG to cause arrhythmias can not be ignored. To develop safer and effective drugs, it is necessary to understand the interactions between drugs and hERG channels and the molecular mechanism behind this high affinity. In this review, we focus on the biochemical and molecular mechanistic aspects of related drug blockade in the hERG trying to provide insights into the QT interval prolongation caused by potential therapeutic drugs for COVID-19 and hope to weigh the risks and benefits when using related drugs.

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“…In other words, it would be surmised that the low bioavailability of BBR is likely to keep the safety of its use clinically. Moreover, BBR in combination with the statins can to some extent increase cardiotoxicity due to the inhibition against CYP3A4 and hERG channel 10) .…”

Section: Introductionmentioning

confidence: 99%

Discovery of C-9 Modified Berberine Derivatives as Novel Lipid-Lowering Agents

Pan

et al. 2021

CHEMICAL & PHARMACEUTICAL BULLETIN

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Berberine (BBR), a kind of quaternary ammonium benzylisoquinoline alkaloids with multiple pharmacological activities, has been regarded as a promising lipid-lowering agent in the field of drug repurposing. Particularly, the chemical modification at the C-9 position of BBR can remarkably improve its lipid-lowering efficacy. In this study, thirteen novel BBR derivatives were rationally designed, synthesized, and evaluated by preliminary pharmacological tests. The results showed that most compounds exhibited more potent hypolipidemic activities when compared with BBR and simvastatin. Among these compounds, compound 2h-1 and 2h-2 exhibited better activity profiling in these four tests involving with inhibition of total cholesterol (TCHO), triglyceride (TG), and low-density lipoprotein cholesterol (LDLC) and the increase of high-density lipoprotein cholesterol (HDLC). Correspondingly, the BBR analogs with 9-O-cinnamic moiety probably exhibited potent lipid-lowering activity, and should be exploited as an important versatile template for the development of BBR-like lipid-lowering agents.

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The enhancement of cardiotoxicity that results from inhibiton of CYP 3A4 activity and hERG channel by berberine in combination with statins

Cited by 28 publications

References 28 publications

Evaluation of cytochrome P450 3A4‑mediated drug‑drug interaction potential between P2Y12 inhibitors and statins

Evaluation of cytochrome P450 3A4‑mediated drug‑drug interaction potential between P2Y12 inhibitors and statins

Potential therapeutic drugs for COVID-19 risk prolonging QT interval targeting hERG channel

Discovery of C-9 Modified Berberine Derivatives as Novel Lipid-Lowering Agents

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