Potential Herb-drug Interactions Research Articles

A Systematic Review of Herbal Interventions for the Management of Cardiovascular Diseases.

Cardiovascular diseases represent a significant global health burden, necessitating diverse approaches for effective management. Herbal interventions have gained attention as potential adjuncts or alternatives to conventional therapies due to their perceived safety and therapeutic potential. This structured abstract provides a comprehensive review of herbal interventions for the management of CVDs, summarising key findings, mechanisms of action, and clinical implications. This systematic review aims to evaluate the impact of various herbal interventions employed for managing cardiovascular diseases. We conducted an extensive literature search across electronic databases, including PubMed, Scopus, and Web of Science, from inception to 2022. Studies were included if they investigated the use of herbal remedies for preventing or treating CVDs. Data extraction and synthesis focused on botanical sources, active compounds, mechanisms of action, and clinical outcomes. Numerous herbal interventions have demonstrated promising cardiovascular benefits. A number of medicinal herbs well identified to treat CVD are Moringaoleifera, Ginseng, Ginkgo biloba, Celosia argentea, Gongronematrifolium, Gynostemmapentaphyllum, Bombaxceiba, Gentianalutea, Allium sativum, Crataegusspp, Curcuma longa, Camellia sinensis, and Zingiberofficinale. Mechanistic insights reveal that herbal interventions often target multiple pathways involved in CVD pathogenesis. These mechanisms encompass anti-inflammatory, antioxidant, anti-thrombotic, anti-hypertensive, and lipid-lowering effects. Additionally, some herbs enhance endothelial function, promote nitric oxide production, and exert vasodilatory effects, contributing to improved cardiovascular health. Clinical studies have provided evidence of the efficacy of certain herbal interventions in reducing CVD risk factors and improving patient outcomes. However, more rigorous, large-scale clinical trials are needed to establish their long-term safety and effectiveness. It is crucial to consider potential herb-drug interactions and standardise dosages for reliable therapeutic outcomes. This comprehensive review highlights the potential of herbal interventions as valuable adjuncts or alternatives for managing cardiovascular diseases. Herbal remedies offer diverse mechanisms of action, targeting key CVD risk factors and pathways. While promising, their clinical utility warrants further investigation through well-designed trials to establish their safety and efficacy, paving the way for integrated approaches to cardiovascular disease management. Healthcare providers and patients should engage in informed discussions about the use of herbal interventions alongside conventional therapies in the context of CVD prevention and treatment.

Pharmacokinetic analysis of antiviral drug ritonavir across the blood–brain barrier and its interaction with Scutellaria baicalensis using multisite microdialysis in rats

Ritonavir, an excellent inhibitor of CYP3A4, has recently been combined with nirmatrelvir to form Paxlovid for the treatment of severe acute respiratory syndrome coronavirus 2 infections. The root of Scutellaria baicalensis Georgi (S. baicalensis), a traditional Chinese medicinal (TCM) herb commonly used to treat heat/inflammation in the lung and digestive tracts, which are major organs targeted by viral infections, contains flavones that can influence the CYP3A metabolism pathway. To investigate the ability of ritonavir to cross the bloodbrain barrier (BBB) and its potential herb-drug interactions with an equivalent TCM clinical dose of S. baicalensis, multisite microdialysis coupled with an LCMS/MS system was developed using rat model. Pretreatment with S. baicalensis extract for 5 days, which contains less flavones than those used in previous studies, had a significant influence on ritonavir, resulting in a 2-fold increase in the total concentration of flavones in the blood and brain. Treatment also boosted the maximum blood concentration of flavones by 1.5-fold and the maximum brain concentration of flavones by 2-fold, all the while exerting no noticeable influence on the transfer ratio across the bloodbrain barrier. These experimental results demonstrated that the use of a typical traditional Chinese medicinal dose of S. baicalensis is sufficient to influence the metabolic pathway and synergistically increase the concentration of ritonavir in rats.

Exploring the Potential of Herbal Remedies in Indonesia: Insights From the Wellness Index in the Jamu Registry Database

IntroductionIn order to assess the effectiveness of herbal treatments, we examined Wellness Index (WI) scores to gain a better understanding of how herbal interventions influence overall well-being. MethodsData were obtained from the Jamu Registry from 2014 to 2018. The improvement in the patient’s health status was evaluated by quantifying the WI score through the utilisation of the WI tool, which was developed by the NIHRD in 2012. This tool is a modification of the WHO’s quality of life short form-36. ResultsFrom the dataset, a total of 1467 patients were analysed. The majority of these patients were diagnosed for hypertension (18%), followed by diabetes mellitus (15.3%), and dyspepsia (12.7%). Among all cases, 65.7% patients were treated with herbal medicine. In general, there was a notable improvement in the WI score during subsequent follow-up visits. Notably, upon closer examination, patients treated with a combination of conventional and herbal therapies did not exhibit a significant improvement in their wellness (QoL) index when compared to those receiving herbal therapy alone. ConclusionsOur study indicates that herbal medicine may have a positive impact on the improvement of patients’ quality of life. However, it is essential to highlight that the combination of herbal remedies with conventional medicines should be considered with caution due to the potential for herb-drug interactions.

Network pharmacology and bioinformatics based investigation of Phyllanthus fraternus: herb-drug interaction study

Phyllanthus fraternus (PF), a plant from the Euphorbiaceae family, is used extensively in ayurvedic formulations for its significant medicinal properties. When PF is administered alongside conventional drugs, there could be potential herb-drug interactions between the active compounds and the genes involved in drug transport and metabolism. Hence, this study was designed to investigate potential herb-drug interactions, focusing on elucidating their functional and pharmacological mechanisms, using an integrated approach of metabolite profiling and network pharmacology. We utilized LC-MS to generate metabolite profiling of PF and network pharmacology for predicting key targets and pathways. This comprehensive analysis involved the construction of networks illustrating the relationships among compounds, targets, and pathways and the exploration of protein-protein interactions and protein-ligand interactions. In this study, a total of 79 compounds were identified in LC-MS, such as alkaloids, steroids, saponins, flavonoids, lignans, phenolic acids, tannins, terpenoids, and fatty acids. The identified compound’s physicochemical properties were predicted using SwissADME. Network analysis predicted 1076 PF-related genes and 1497 genes associated with drug transport and metabolism, identifying 417 overlapping genes, including 51 related to drug transport and metabolism. Based on the degree of interaction the hub targets like ABCB1, CYP1A1, CYP1A2, CYP2C9, and CYP3A4 were identified. In the compound-target-pathway network, 2,4-bis(1,1-dimethyl ethyl)-phenol; 5-Methoxy-N-[(5-Methylpyridin-2-yl) sulfonyl]-1h-Indole-2-Carboxamide; and E,E,Z-1,3,12-Nonadecatriene-5,14-diol possessed more interactions with the targets. This study helps identify bioactive compounds, essential targets, and pathways potentially implicated in these interactions, laying the foundation for future studies (in vitro and in vivo) to verify their potential to explore their clinical implications.Communicated by Ramaswamy H. Sarma

Signal Detection and Assessment of Herb-Drug Interactions: Saudi Food and Drug Authority Experience.

Numerous investigations on herbal medicine that have been undertaken in the past several years demonstrate the general acceptance of its safety. The Saudi Food and Drug Authority (SFDA) established the Herb-Drug Interaction (HDI) project to detect and assess potential HDIs to ensure safety. The aim is to detect safety signals and assess them based on available evidence. First, SFDA-registered herbal products (n=30) were selected and prioritized based on commonly used herbs. Second, reported potential HDIs were retrieved from the World Health Organization global database of individual case safety reports (VigiBase), AdisInsight®, and the Natural Medicines database. We excluded drugs non-registered by SFDA and labeled interactions in the product information of SFDA, the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA). Finally, a comprehensive evaluation of potential HDIs was carried out using several evidence sources: literature, global cases, local cases, and other relevant documents. The Drug Interaction Probability Scale (DIPS) scale was used to assess the probability of a causal relationship between the interacting herb and drug and the event. The search yielded 566 potential signals, and 41 had published evidence and were referred for assessment. The assessment results using DIPS were: 22 possible (53.6 %), 7 probable (17%), and 12 doubtful (29.2%) interactions. The recommendation was to include probable HDIs in the product information, including turmeric-tacrolimus, etoposide-Echinacea, Ginkgo biloba-ibuprofen, green tea-warfarin, and licorice-thiazides interactions. The HDI project assessed the screening and identification of potential HDIs. The action plan of this project can be used in post-marketing activities to identify potential drug interactions.

Medicinal Herbs for the Treatment of Peptic Ulcers

Abstract: Peptic ulcers are common gastrointestinal disorders characterized by the erosion of the stomach lining, duodenum, or esophagus. Conventional treatments, such as proton pump inhibitors and antibiotics for Helicobacter pylori eradication, have been the mainstay of therapy. However, the emergence of drug resistance and potential side effects have led to the exploration of alternative and complementary approaches, including medicinal herbs. This comprehensive review examines the potential use of medicinal herbs in the management of peptic ulcers. Ten herbal remedies, including Liquorice, Slippery Elm, Marshmallow Root, Aloe Vera, Chamomile, Ginger, Turmeric, Meadowsweet, Fenugreek, and Cabbage, are analyzed for their therapeutic properties and scientific research findings. These herbs have demonstrated anti-inflammatory, antimicrobial, and mucoprotective effects that may support ulcer healing and symptom relief. Herbal formulations, such as teas, capsules, tablets, and extracts, offer convenient delivery methods for patients seeking herbal remedies. However, safety considerations and potential herb-drug interactions must be carefully monitored. Integrating herbal remedies with conventional treatments presents a comprehensive approach to peptic ulcer management. By combining these therapies, patients may experience enhanced therapeutic outcomes and improved quality of life. Dietary recommendations also play a crucial role, with the inclusion of soothing and beneficial foods, while avoiding trigger foods that may exacerbate symptoms. As the evidence base grows, collaborative efforts between traditional herbal medicine practitioners and mainstream medical professionals are vital to ensure safe and effective integration.

Prevalence and predictors of traditional medicine use among persons with diabetes in Africa: a systematic review.

The utilization of traditional medicine (TM) is prevalent among the general population in Africa; however, its use among individuals with diabetes in the region remains underdocumented. This review aimed to synthesize the available literature to identify the prevalence and predictors of TM use among persons with diabetes in Africa. A systematic search was conducted across multiple databases, including MEDLINE, Embase, CINAHL, and AMED, covering studies published from 2000 to April 2023. Of 1560 records identified, 24 articles met the inclusion criteria. The prevalence of TM use varied significantly, ranging from 12.4% to 77.1%, with a median prevalence of 50%. TM was commonly used concurrently with conventional medicine (CM) (35.4-88.4%), with a majority (63.8-91.3%) not disclosing TM use to healthcare providers. Female gender, long diabetes duration, use of oral antiglycaemic medication and family history of diabetes emerged as the most common factors that predicted the use of TM. This review highlights the widespread use of TM among individuals with diabetes in Africa, often in conjunction with CM. The high prevalence of undisclosed TM use emphasizes the urgent need for healthcare providers to actively inquire about TM use during clinical consultations to address potential herb-drug interactions and adverse effects.

Drug-Herb Synergistic Interactions between Clopidogrel and Natural Medicine.

Natural medicine (NM) has been used since ancient times for therapeutic purposes worldwide. Presently, the combination of clopidogrel and NM with a reasonable synergistic effect has gained increasing acceptance in clinical therapeutics. Here, we have performed a comprehensive retrieval of literature published in both English and Chinese databases until August 1, 2022, studying the synergistic interactions of clopidogrel and NM through pharmacokinetic/pharmacodynamic (PK-PD) analyses. We retrieved 7, 3, and 5 studies on PK analysis and 3, 3, and 8 studies on PD analysis for the interaction of clopidogrel with single herbal medicines, bioactive compounds, and herbal prescriptions, respectively. Most studies on NM have been found to mainly focus on preclinical observations, and there have been fewer clinical PK analyses. A potential drug-herb interaction has been observed to occur when clopidogrel and NM were metabolized by an enzyme network comprising P-gp, CES1, and CYP450. In contrast, most PD studies have focused on clinical observations, and few preclinical findings have been reported. Some cases have suggested that the combination of the two types of drugs would alter the antiplatelet efficacy and adverse effects. Studies on PK, however, have shown significant or slightly varying results for the drug prototype and its metabolites. In the combination therapies, the interaction between clopidogrel and NM was found to alter antiplatelet aggregation pathways and P2Y12 receptor function.

Potential herb‒drug interactions between anti-COVID-19 drugs and traditional Chinese medicine.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide. Effective treatments against COVID-19 remain urgently in need although vaccination significantly reduces the incidence, hospitalization, and mortality. At present, antiviral drugs including Nirmatrelvir/Ritonavir (PaxlovidTM), Remdesivir, and Molnupiravir have been authorized to treat COVID-19 and become more globally available. On the other hand, traditional Chinese medicine (TCM) has been used for the treatment of epidemic diseases for a long history. Currently, various TCM formulae against COVID-19 such as Qingfei Paidu decoction, Xuanfei Baidu granule, Huashi Baidu granule, Jinhua Qinggan granule, Lianhua Qingwen capsule, and Xuebijing injection have been widely used in clinical practice in China, which may cause potential herb-drug interactions (HDIs) in patients under treatment with antiviral drugs and affect the efficacy and safety of medicines. However, information on potential HDIs between the above anti-COVID-19 drugs and TCM formulae is lacking, and thus this work seeks to summarize and highlight potential HDIs between antiviral drugs and TCM formulae against COVID-19, and especially pharmacokinetic HDIs mediated by metabolizing enzymes and/or transporters. These well-characterized HDIs could provide useful information on clinical concomitant medicine use to maximize clinical outcomes and minimize adverse and toxic effects.

Influence of Gegenqinlian decoction on pharmacokinetics and pharmacodynamics of saxagliptin in type 2 diabetes mellitus rats.

Gegenqinlian decoction (GQD) is a classic prescription of traditional Chinese medicine (TCM), which originated from Shanghanlun. The combination of GQD and hypoglycemic drugs (saxagliptin, Sax, metformin) is often used to treat Type 2 diabetes mellitus (T2DM) in TCM clinics. However, the herb-drug interactions (HDIs) between GQD and hypoglycemic drugs are still unclear. In order to determine the safety of the combination, we assessed the influences of GQD on the pharmacokinetics and pharmacodynamics of Sax in T2DM rats. The plasma concentration of Sax (5mg/kg) pretreated with GQD (freeze-dried powder, 1.35g/kg) or not was determined by high-performance liquid chromatography (HPLC), and pharmacokinetics parameters were calculated. The influence of GQD on the pharmacodynamics of Sax was investigated by detecting the levels of weight, (see abbreviations list) OGTT, TC, TG, LDL-C, HDL-C, FBG, FINS, HOMA-IR, QUICKI, AST, ALT, and the liver coefficient. The Cmax , AUC0-t ,and AUC0-∞ of Sax increased significantly in the combination group whether in normal or T2DM rats. The results of pharmacodynamics showed that the weight of rats in each treatment group increased. FBG, TC, TG, LDL-C, and HOMA-IR decreased, HDL-C, FINS, and QUICKI increased significantly (p<0.05) compared with the model control group. The result showed that the combination of GQD and Sax could not only improve the hypoglycemic effect but also increase the plasma exposure of Sax. The potential HDIs between GQD and Sax should be taken into consideration in clinics. Moreover, for the complexity of the human compared with experimental animals, as well as genetic differences, the in-depth study should be carried out to assess the uniformity of the pharmacokinetics and pharmacodynamics between rats and humans.

Inhibitory effects of herbal medicines with claimed anticancer indications on cytochrome P450—An evaluation of drug-herb interactions risk

Herbs have the potential to interact with conventional medicines or each other upon concurrent administration. This can be at the level of absorption, distribution, metabolism and excretion (ADME). With an estimation that 80% of the population in poor regions of the world utilise herbal medicines for primary healthcare, there is a likelihood that some people will take both herbal and conventional medicines. This could present a risk for herb-drug interactions (HDI) at the various levels of the ADME process. Most common HDI have been observed at metabolism level involving inhibition or induction of the major drug metabolising liver enzymes called cytochrome P450s. In this study, we investigated the inhibitory effects of Parinari curatellifolia (MC), Fluggea virosa (ST), Garcinia livingstonei (MT), Pterocarpus angolensis (M), Tapinanthus quequensis (MF) and Cussonia arborea (GM) on recombinant CYP1A2, CYP2D6, CYP2C9 and CYP2C19. Plate based fluorescent assays were used to follow enzyme activity. Inhibition was determined at 5 mg/ml and 100 mg/ml of herbal extract, with IC50 determined for herbs that showed potent inhibition. A total of 10 out of 13 extracts showed significant inhibitory effects. Pterocarpus angolensis(bark), Fluggea virossa (leaf), Cussonia arborea(bark), Parinari curatellifollia (root) had very potent effects on CYP1A2 as indicated by an IC50 of <9.9 µg/ml. Based on the worst-case-scenario of complete absorption and exposure, these herbs are predicted to result in HDI if co-administered with medicines which depend on the affected CYPs for metabolism and elimination. Significance of the main findingsThere is a potential threat of drug toxicities due to drug-herb interactions for patients undergoing chemotherapy or taking other medications where co-morbidities exist during chemotherapy. Drugs that are substrates of CYP1A2 should be administered with caution for patients who are taking the herbs which have been studied in this research as risk for drug toxicities may be high. The findings act as a guide to medical doctors and patients in evaluating potential for herb-drug interactions during prescribing medications which are substrates for the studied CYPs.

Potential pharmacokinetic interactions with concurrent use of herbal medicines and a ritonavir-boosted COVID-19 protease inhibitor in low and middle-income countries.

The COVID-19 pandemic sparked the development of novel anti-viral drugs that have shown to be effective in reducing both fatality and hospitalization rates in patients with elevated risk for COVID-19 related morbidity or mortality. Currently, nirmatrelvir/ritonavir (Paxlovid™) fixed-dose combination is recommended by the World Health Organization for treatment of COVID-19. The ritonavir component is an inhibitor of cytochrome P450 (CYP) 3A, which is used in this combination to achieve needed therapeutic concentrations of nirmatrelvir. Because of the critical pharmacokinetic effect of this mechanism of action for Paxlovid™, co-administration with needed medications that inhibit or induce CYP3A is contraindicated, reflecting concern for interactions with the potential to alter the efficacy or safety of co-administered drugs that are also metabolized by CYP3A. Some herbal medicines are known to interact with drug metabolizing enzymes and transporters, including but not limited to inhibition or induction of CYP3A and P-glycoprotein. As access to these COVID-19 medications has increased in low- and middle-income countries (LMICs), understanding the potential for herb-drug interactions within these regions is important. Many studies have evaluated the utility of herbal medicines for COVID-19 treatments, yet information on potential herb-drug interactions involving Paxlovid™, specifically with herbal medicines commonly used in LMICs, is lacking. This review presents data on regionally-relevant herbal medicine use (particularly those promoted as treatments for COVID-19) and mechanism of action data on herbal medicines to highlight the potential for herbal medicine interaction Herb-drug interaction mediated by ritonavir-boosted antiviral protease inhibitors This work highlights potential areas for future experimental studies and data collection, identifies herbal medicines for inclusion in future listings of regionally diverse potential HDIs and underscores areas for LMIC-focused provider-patient communication. This overview is presented to support governments and health protection entities as they prepare for an increase of availability and use of Paxlovid™.

Herbal Medicines as Adjuvants for the Treatment of Chemotherapy-Induced Diarrhea.

Chemotherapeutic drugs used in cancer treatment often result in gastrointestinal toxicity, notably diarrhea, impacting patients' quality of life. Complementary and Alternative Medicine (CAM) has garnered increasing interest as an alternative to conventional approaches as a potential solution for managing chemotherapyinduced diarrhea (CID). To summarize current research focusing on herbal medicines as adjuvant therapy to prevent or treat chemotherapy-induced diarrhea, including clinical assessments, mechanism of actions, active components, and potential pharmacokinetic interactions between herbal medicines and chemotherapeutic drugs. We performed the literature review from PubMed, CNKI, Google Scholar, Web of Science, and Scopus using "Chemotherapy", "Diarrhea," and "Complementary and Alternative Medicine" as the search keywords. Using herbal medicines as adjuvants provides an effective approach to treating or preventing CID with improved or unaffected antitumor activity of chemotherapeutic drugs. Among these herbal formulations, scutellaria, ginger, and ginseng are the most frequently used herbs in the prescriptions for CID. The main antidiarrheal components in herbs include wogonin, baicalin, chrysin, quercetin, gingerol, and ginsenosides. These herbs, formulations, and bioactive components relieved CID through different mechanisms, including directly decreasing local drug exposure, anti-inflammation, inhibiting epithelial apoptosis, or promoting epithelium stem cell regeneration. The application of herbal medicines as adjunctive therapies showed efficacy in preventing or treating CID in multiple clinical trials. However, more well-designed clinical studies are expected to validate the results further. Despite some clinical studies demonstrating that certain herbal medicines could potentially attenuate CID and improve efficacy, it remains necessary to evaluate herbal safety. The interactions between herbs and drugs are also potential concerns, but few clinical trials have focused on investigating this aspect. In clinical practise, herbal medications show potential as adjuvant treatments for gastrointestinal toxicities induced by chemotherapy, particularly diarrhoea. Further well-designed clinical studies are needed to validate their efficacy, ensure safety, and explore potential drug-herb interactions.

Evaluation of the potential herb-drug interaction between Bojungikki-tang and PD-L1 immunotherapy in a syngeneic mouse model.

Atezolizumab (a PD-L1 inhibitor) has shown remarkable efficacy and tolerability in various cancer types. Despite its efficacy and safety, atezolizumab monotherapy has limitations, such as acquired resistance and adverse events. Bojungikki-tang (BJIKT) is an herbal decoction widely prescribed in Asian countries and used to treat cancer-related symptoms including fatigue, appetite loss, gastrointestinal disorders, and other side effects from cancer therapy. Due to its immunomodulatory effects, Bojungikki-tang has been investigated as a combined treatment with anticancer agents. We evaluated the potential drug-drug interaction (DDI) between Bojungikki-tang and the anti-PD-L1 antibody based on the Food and Drug Administration (FDA) guidelines. In the study, we conducted an in vivo drug-drug interaction study using a syngeneic mouse model of CMT-167 in C57BL/6. We then determined the antibody concentrations to evaluate the pharmacokinetic (PK) drug-drug interaction and measured variable biomarkers related to therapeutic efficacy and immune response. The pharmacodynamic (PD) drug-drug interaction study investigated changes in response between anti-PD-L1 antibody monotherapy and combination therapy. Using the pharmacokinetic and pharmacodynamic data, we conducted a statistical analysis to assess drug-drug interaction potential. In the presence of Bojungikki-tang, the pharmacokinetic characteristics of the anti-PD-L1 antibody were not changed. This study suggested that combination treatment with Bojungikki-tang and atezolizumab is a safe treatment option for non-small cell lung cancer. Clinical studies are warranted to confirm this finding.

Rapid high performance liquid chromatography method for erlotinib quantification in vitro: Application to study the effect of resveratrol on metabolism and cellular uptake of erlotinib.

Erlotinib is a selective epidermal growth factor receptor inhibitor that is used for the treatment of non-small cell lung cancer and pancreatic cancer. Its metabolism is mainly mediated by cytochrome P450 3A (CYP 3A). Resveratrol, a natural compound found in many plants and supplements, is known to inhibit CYP3A enzyme, therefore, it may act as an inhibitor for the metabolism of erlotinib. Development of a rapid high performance liquid chromatography with photodiode array detection (HPLC-PDA) method for the quantification of erlotinib in liver microsomes and cancer cells and its application to study resveratrol effect on metabolism and cellular uptake of erlotinib. HPLC-PDA was used to develop an efficient bioanalytical method with a 2.5-min runtime preceded by a simple protein precipitation step. The method was validated according to the European Medicines Agency guidelines. Erlotinib metabolic stability and resveratrol effect on erlotinib metabolite formation were evaluated in rat liver microsomes. Furthermore, the method was used to measure the intracellular concentrations of erlotinib in cancer colorectal cells and investigating resveratrol effect on the cellular uptake of erlotinib. A rapid HPLC-PDA method was developed and validated for the first time to address potential drug interaction of erlotinib with resveratrol. Resveratrol was a strong inhibitor of erlotinib metabolism in vitro with IC50  = 4.03 μM. Resveratrol, however, had no effect on erlotinib cellular uptake after 1h incubation in human colorectal cancer cells. The study suggests that resveratrol may produce a potential herb-drug interaction with erlotinib at the metabolism level and should be investigated in patients in the clinic.

Evaluation potential effects of Picroside II on cytochrome P450 enzymes in vitro and in vivo

Ethnopharmacology relevancePicrorhiza scrophulariiflora Pennell, a well-known Chinese herb, has been traditionally utilized as an antioxidant and anti-inflammatory agent. One of its main bioactive components is Picroside II, a glycoside derivative. However, there is limited information on the effects of Picroside II on the activity of cytochrome P450 (CYP) enzymes nor on potential herb-drug interactions are rarely studied. Aim of the studyThe purpose of the study was to investigate the effects of Picroside II on the activity of cytochrome P450 enzymes in vitro and in vivo and its potential herb-drug interactions. Materials and methodsSpecific probe substrates were employed to assess the effect of Picroside II on the activity of P450 enzymes. The inhibitory effects of Picroside II on CYP enzymes were assayed both in human (i.e., 1A, 2C9, 2C19, 2D6, 2E1, and 3A) and rat (i.e., 1A, 2C6/11, 2D1, 2E1, and 3A) liver microsomes in vitro. The inductive effects were investigated in rats following oral gavage of 2.5 mg/kg and 10 mg/kg Picroside II. A specific Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) method was developed to determine the formation of specific metabolites. ResultsEnzyme inhibition results showed that Picroside II (0.5–200 μM) had no evident inhibitory effects on rat and human liver microsomes in vitro. Interestingly, the administration of multiple doses of 10 mg/kg Picroside II inhibited the activity of CYP2C6/11 by reducing the rate of formation of 4-hydroxydiclofenac and 4-hydroxymephenytoin, while Picroside II at 2.5 mg/kg increased the activity of CYP3A by promoting the formation of 1-hydroxymidazolam and 6-hydroxychlorzoxazone in rats. In addition, there were negligible effects on CYP1A, CYP2D1, and CYP2E1 in rats. ConclusionsThe results indicated that Picroside II modulated the activities of CYP enzymes and was involved in CYP2C and CYP3A medicated herb-drug interactions. Therefore, careful monitoring is necessary when Picroside II is used in combination with related conventional drugs.

In Vitro Hepatic Models to Assess Herb-Drug Interactions: Approaches and Challenges.

A newfound appreciation for the benefits of herbal treatments has emerged in recent decades. However, herbal medication production still needs to establish standardized protocols that adhere to strict guidelines for quality assurance and risk minimization. Although the therapeutic effects of herbal medicines are extensive, the risk of herb-drug interactions remains a serious concern, limiting their use. Therefore, a robust, well-established liver model that can fully represent the liver tissue is required to study potential herb-drug interactions to ensure herbal medicines' safe and effective use. In light of this, this mini review investigates the existing in vitro liver models applicable to detecting herbal medicines' toxicity and other pharmacological targets. This article analyzes the benefits and drawbacks of existing in vitro liver cell models. To maintain relevance and effectively express the offered research, a systematic strategy was employed to search for and include all discussed studies. In brief, from 1985 to December 2022, the phrases "liver models", "herb-drug interaction", "herbal medicine", "cytochrome P450", "drug transporters pharmacokinetics", and "pharmacodynamics" were combined to search the electronic databases PubMed, ScienceDirect, and the Cochrane Library.

Identification of PXR Activators from Uncaria Rhynchophylla (Gou Teng) and Uncaria Tomentosa (Cat's Claw).

Uncaria rhynchophylla (Gou Teng) and Uncaria tomentosa (cat's claw) are frequently used herbal supplements in Asia and America, respectively. Despite their common usage, information is limited regarding potential herb-drug interactions associated with Gou Teng and cat's claw. The pregnane X receptor (PXR) is a ligand-dependent transcription factor that regulates cytochrome P450 3A4 (CYP3A4) expression and contributes to some known herb-drug interactions. A recent study found that Gou Teng induces CYP3A4 expression, but its mechanism is unknown. Cat's claw has been determined as a PXR-activating herb, but the PXR activators in cat's claw have not been identified. Using a genetically engineered PXR cell line, we found that the extracts of Gou Teng and cat's claw can dose-dependently activate PXR and induce CYP3A4 expression. We next used a metabolomic approach to profile the chemical components in the extracts of Gou Teng and cat's claw followed by screening for PXR activators. Four compounds, isocorynoxeine, rhynchophylline, isorhynchophylline, and corynoxeine, were identified as PXR activators from both Gou Teng and cat's claw extracts. In addition, three more PXR activators were identified from the extracts of cat's claw, including isopteropodine, pteropodine, and mitraphylline. All seven of these compounds showed the half-maximal effective concentration <10 µM for PXR activation. In summary, our work determined Gou Teng as a PXR-activating herb and discovered novel PXR activators from Gou Teng as well as cat's claw. SIGNIFICANCE STATEMENT: This study's data can be used to guide the safe use of Gou Teng and cat's claw by avoiding PXR-mediated herb-drug interactions.

Inhibitory effect of Selaginella doederleinii hieron on human cytochrome P450.

Introduction: Selaginella doederleinii Hieron is a traditional Chinese herbal medicine, the ethyl acetate extract from Selaginella doederleinii (SDEA) showed favorable anticancer potentials. However, the effect of SDEA on human cytochrome P450 enzymes (CYP450) remains unclear. To predict the herb-drug interaction (HDI) and lay the groundwork for further clinical trials, the inhibitory effect of SDEA and its four constituents (Amentoflavone, Palmatine, Apigenin, Delicaflavone) on seven CYP450 isoforms were investigated by using the established CYP450 cocktail assay based on LC-MS/MS. Methods: Appropriate substrates for seven tested CYP450 isoforms were selected to establish a reliable cocktail CYP450 assay based on LC-MS/MS. The contents of four constituents (Amentoflavone, Palmatine, Apigenin, Delicaflavone) in SDEA were determined as well. Then, the validated CYP450 cocktail assay was applied to test the inhibitory potential of SDEA and four constituents on CYP450 isoforms. Results: SDEA showed strong inhibitory effect on CYP2C9 and CYP2C8 (IC50 ≈ 1μg/ml), moderate inhibitory effect against CYP2C19, CYP2E1 and CYP3A (IC50 < 10μg/ml). Among the four constituents, Amentoflavone had the highest content in the extract (13.65%) and strongest inhibitory effect (IC50 < 5μM), especially for CYP2C9, CYP2C8 and CYP3A. Amentoflavone also showed time-dependent inhibition on CYP2C19 and CYP2D6. Apigenin and Palmatine both showed concentration-dependent inhibition. Apigenin inhibited CYP1A2, CYP2C8, CYP2C9, CYP2E1 and CYP3A. Palmatine inhibited CYP3A and had a weak inhibitory effect on CYP2E1. As for Delicaflavone, which has the potential to develop as an anti-cancer agent, showed no obvious inhibitory effect on CYP450 enzymes. Conclusion: Amentoflavone may be one of the main reasons for the inhibition of SDEA on CYP450 enzymes, the potential HDI should be considered when SDEA or Amentoflavone were used with other clinical drugs. On the contrast, Delicaflavone is more suitable to develop as a drug for clinical use, considering the low level of CYP450 metabolic inhibition.

Phytochemical Comparison of Medicinal Cannabis Extracts and Study of Their CYP-Mediated Interactions with Coumarinic Oral Anticoagulants

Introduction: Treatment with cannabis extracts for a variety of diseases has gained popularity. However, differences in herb-drug interaction potential of extracts from different plant sources are poorly understood. In this study, we provide a characterization of cannabis extracts prepared from four cannabis chemotypes and an in vitro assessment of their Cytochrome P450 (CYP)-mediated herb-drug interaction profiles. Methods: Plant extracts were either commercially obtained or prepared using ethanol as solvent, followed by overnight decarboxylation in a reflux condenser system. The extracts were characterized for their cannabinoid content using NMR and HPLC-PDA-ELSD-ESIMS. CYP inhibition studies with the cannabis extracts and pure cannabinoids (tetrahydrocannabinol [THC] and cannabidiol [CBD]) were performed using pooled, mixed gender human liver microsomes. Tolbutamide and testosterone were used as specific substrates to assess the inhibitory potential of the extracts on CYP2C9 and CYP3A4, and the coumarinic oral anticoagulants warfarin, phenprocoumon, and acenocoumarol were studied as model compounds since in vivo herb-drug interactions have previously been reported for this compound class. Results: In accordance with the plant chemotypes, two extracts were rich in THC and CBD (at different proportions); one extract contained mostly CBD and the other mostly cannabigerol (CBG). Residual amounts of the corresponding acids were found in all extracts. The extracts with a single major cannabinoid (CBD or CBG) inhibited CYP2C9- and CYP3A4-mediated metabolism stronger than the extracts containing both major cannabinoids (THC and CBD). The inhibition of CYP3A4 and CYP2C9 by the extract containing mostly CBD was comparable to their inhibition by pure CBD. In contrast, the inhibitory potency of extracts containing both THC and CBD did not correspond to the combined inhibitory potency of pure THC and CBD. Although being structural analogs, the three coumarin derivatives displayed major differences in their herb-drug interaction profiles with the cannabis extracts and the pure cannabinoids. Conclusion: Despite the fact that cannabinoids are the major components in ethanolic, decarboxylated cannabis extracts, it is difficult to foresee their herb-drug interaction profiles. Our in vitro data and the literature-based evidence on in vivo interactions indicate that cannabis extracts should be used cautiously when co-administered with drugs exhibiting a narrow therapeutic window, such as coumarinic anticoagulants, regardless of the cannabis chemotype used for extract preparation.