Potential Herb-drug Interactions Research Articles

Critical pharmacokinetic and pharmacodynamic drug-herb interactions in rats between warfarin and pomegranate peel or guava leaves extracts

BackgroundIn-depth information of potential drug-herb interactions between warfarin and herbal compounds with suspected anticoagulant blood thinning effects is needed to raise caution of concomitant administration. The current study aimed to investigate the impact of co-administration of pomegranate peel and guava leaves extracts, including their quality markers namely; ellagic acid and quercetin, respectively, on warfarin’s in vivo dynamic activity and pharmacokinetic actions, in addition to potential in vitro cytochrome P450 enzymes (CYP) inhibition.MethodsInfluence of mentioned extracts and their key constituents on warfarin pharmacodynamic and kinetic actions and CYP activity were evaluated. The pharmacodynamic interactions were studied in Sprague Dawley rats through prothrombin time (PT) and International Normalized Ratio (INR) measurements, while pharmacokinetic interactions were detected in vivo using a validated HPLC method. Furthermore, potential involvement in CYP inhibition was also investigated in vitro on isolated primary rat hepatocytes.ResultsPreparations of pomegranate peel guava leaf extract, ellagic acid and quercetin in combination with warfarin were found to exert further significant increase on PT and INR values (p < 0.01) than when used alone (p < 0.05). Pomegranate peel extract showed insignificant effects on warfarin pharmacokinetics (p > 0.05), however, its constituent, namely, ellagic acid significantly increased warfarin Cmax (p < 0.05). Guava leaves extract and quercetin resulted in significant increase in warfarin Cmax when compared to control (p < 0.01). Furthermore, guava leaves extract showed a significant effect on changing the AUC, CL and Vz. Significant reduction in CYP2C8, 2C9, and 3A4 was seen upon concomitant use of warfarin with ellagic acid, guava leaves and quercetin, unlike pomegranate that insignificantly affected CYP activities.ConclusionAll combinations enhanced the anticoagulant activity of warfarin as the results of in vivo and in vitro studies were consistent. The current investigation confirmed serious drug herb interactions between warfarin and pomegranate peel or guava leaf extracts. Such results might conclude a high risk of bleeding from the co-administration of the investigated herbal drugs with warfarin therapy. In addition, the results raise attention to the blood-thinning effects of pomegranate peel and guava leaves when used alone.

Regulation of P-glycoprotein by Bajijiasu in vitro and in vivo by activating the Nrf2-mediated signalling pathway

Context: Bajijiasu (BJJS), a main bioactive compound from Morinda officinalis F.C. How. (Rubiaceae), is widely administered concomitantly with other drugs for treating male impotence, female infertility, fatigue, chronic rheumatism, depression, etc.Objective: This study investigates the regulation of P-glycoprotein (P-gp) by BJJS in vitro and in vivo.Material and methods: HepG2 cells were incubated with BJJS (10, 20 or 40 μM) for 48 h. C57 mice were orally treated with BJJS (25, 50 or 100 mg/kg) for 2 weeks. The protein and mRNA levels of P-gp were measured by using Western blot and real-time PCR, respectively. siNrf2 RNA was used to explore the mediation effects of Nrf2 on the P-gp expression. The efflux activity of P-gp was tested via a flow cytometry.Results: Incubation of HepG2 cells with BJJS at 10, 20, and 40 μM up-regulated the P-gp protein expression by 12.3%, 82.9%, and 134.3%, respectively. Treatment of C57 mice with BJJS at 25, 50 and 100 mg/kg increased the P-gp protein expression by 49.3%, 75.8% and 106.0%, respectively. Incubation of the cells with BJJS at 10, 20 and 40 μM up-regulated the total Nrf2 protein levels by 34.3%, 93.1% and 118.6%, respectively, and also increased the nuclear Nrf2 protein levels by 14.8%, 44.4% and 59.25%, respectively. The total Nrf2 protein levels were increased by 46.3%, 66.5%, and 87.4%, respectively, in the mice exposed to BJJS at 25, 50, and 100 mg/kg. Inhibition of Nrf2 by siRNA diminished the P-gp induction by 25.0%, 33.4%, and 38.7%, respectively, in the cells. In addition, BJJS enhanced the efflux activity of P-gp by 9.6%, 37.1%, and 48.1%, respectively, in the cells.Conclusions: BJJS activates Nrf2 to induce P-gp expression, and enhanced the efflux activity of P-gp. The possibility of potential herb–drug interactions when BJJS is co-administered with other P-gp substrate drugs should be carefully monitored.

Astragali radix and its main bioactive compounds activate the Nrf2-mediated signaling pathway to induce P-glycoprotein and breast cancer resistance protein

Ethnopharmacological relevanceAstragali radix (Huang Qi, HQ), a well-known Chinese herbal medicine, is widely coadministered with many other drugs for treating diseases. The potential herb–drug interactions (HDIs) possibly occur during the combination therapy. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are the crucial targets that mediate the production of HDIs. We previously observed that HQ and its three main bioactive compounds, including Astragaloside IV (AS-IV), calycosin (CS) and formononetin (FMNT), could significantly induce the expression of P-gp and BCRP in HepG2 cells in vitro. However, their modulations on the function of P-gp and BCRP remain unknown; their impact on these two proteins expression in vivo is not clear; the exact regulatory mechanism has also not yet been explored. Aim of the studyThis study aimed to investigate the impact of HQ, AS-IV, CS and FMNT on P-gp and BCRP in vivo, and the exact regulatory mechanism involved. The effects of HQ and these compounds on the function of P-gp and BCRP were also studied. Materials and methodsWild-type C57BL/6 mice and nuclear factor E2-related factor-2 knockout (Nrf2−/−) C57BL/6 mice were orally treated with HQ, AS-IV, CS or FMNT. The protein levels of P-gp and BCRP in the liver of mice were measured by using Western blot and immunohistochemistry. The mRNA levels were measured by using real-time PCR. The activation of the drugs on the antioxidant response element (ARE)–luciferin activity was studied by using reporter assay in a stably transfected HepG2-C8 cells. The efflux activity of P-gp and BCRP in HepG2 cells were tested by using flow cytometer with typical probes. ResultsHQ, AS-IV, CS and FMNT significantly upregulated the P-gp and BCRP expression in the liver of wild-type mice. The induction was significantly reversed in the Nrf2−/− mice. HQ and these compounds significantly increased the Nrf2 expression in wild-type mice. HQ and these compounds also markedly enhanced the ARE-luciferin activity and promoted the nuclear translocation of Nrf2 in cells. Besides, HQ and these compounds significantly enhanced the efflux activity of P-gp and BCRP, and increased the intracellular ATP levels. ConclusionsOur results proved that HQ and its main bioactive compounds could induce the P-gp and BCRP expression through the activation of the Nrf2-mediated signaling pathway. HQ and these compounds also significantly enhanced the efflux activity of P-gp and BCRP, and the increased intracellular ATP levels were likely involved in the increased P-gp and BCRP function. These results suggested that potentially HDIs likely occurred when HQ was used concomitantly with other drugs that are substrates of P-gp and BCRP.

Evaluation of Herb-Drug Interaction of Synacinn™ and Individual Biomarker through Cytochrome 450 Inhibition Assay.

SynacinnTM contains five standardized herbal extracts of Orthosiphon Stamineus (OS), Syzygium polyanthum (SZ), Curcuma xantorrizza (CX), Cinnamomum zeylanicum (CZ) and Andrographis paniculata (AP) and is standardized against phytochemical markers of rosmarinic acid, gallic acid, curcumin, catechin and andrographolide respectively. This herbal medicine has been used as health supplement for diabetes. SynacinnTM is recommended to be consumed as supplement to the diabetic drugs. However, herb-drug interaction of SynacinnTM polyherbal with present drugs is unknown. This study was designed to investigate the effect of SynacinnTM and its individual biomarkers on drug metabolizing enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (Midazolam), CYP3A4 (Testosteron)), to assess its herb-drug interaction potential through cytochrome P450 inhibition assay. This study was conducted using liquid chromatography- tandem mass spectroscopy (LC-MS/MS) using probe substrates using human liver microsomes against CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (Midazolam) and CYP3A4 (Testosteron). Result showed that SynacinnTM at maximum concentration (5000 µg/ml) 100% inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (Midazolam) and CYP3A4 (Testosteron). IC50 values determined were 0.23, 0.60, 0.47, 0.78, 1.23, 0.99, 1.01, and 0.91 mg/ml for CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4 (midazolam) and 3A4 (testosterone), respectively. Meanwhile, all individual biomarkers showed no, less or moderate inhibitory effect towards all the tested CYP450 except for curcumin that showed inhibition of CYP2C8 (91%), CYP2C9 (81%) and CYP2C19 (72%) at 10µM. Curcumin was found to be an active constituent that might contribute to the inhibition of SynacinnTM against CYP2C8, CYP2C9 and CYP2C19. It can be suggested that SynacinnTM can be consumed separately from a drug known to be metabolized by all tested CYP450 enzymes.

Risk assessment of substances used in food supplements: the example of the botanical Gymnemasylvestre.

Botanicals and preparations derived from these are among the substances frequently added to foods and food supplements, yet the safety of many botanicals has not been systematically assessed. In the context of the EU‐FORA fellowship programme, the fellow performed an assessment on the safety of the botanical Gymnema sylvestre, in accordance with EFSA's guidance on the assessment of safety of botanicals. Although preparations of G. sylvestre are marketed as food supplements, they may appeal to people who are suffering from metabolic syndrome and/or diabetes mellitus. A scientific literature search was carried out using PubMed/MEDLINE and EMBASE electronic databases. Experience was gained by the fellow in systematic data extraction from scientific publications, structuring of the data and evaluating toxicological key parameters, outcomes of clinical significance, pharmacokinetic and pharmacodynamic interactions, uncertainties and methodological shortcomings of studies. Limited evidence from toxicological in vivo studies and human clinical studies suggested lack of relevant adverse effects of this botanical. However, human studies provided some indications that certain Gymnema extracts may enhance the glucose‐lowering effects of certain antidiabetic drugs. Considering the uncertainties for the composition of different Gymnema preparations, potential herb–drug interactions and the indications of glucose lowering or hypoglycaemic effects, the use of Gymnema‐based food supplements in combination with authorised antidiabetic drugs may be associated with risks. The procedures learned for the safety evaluation of Gymnema may be similarly applied by the fellow for the risk assessment of other substances with nutritional or physiological effect added to foods and food supplements. Furthermore, apart from learning by conducting exercises in risk assessment, the fellow was able to develop other skills (e.g. communication skills), diversify his competencies and expand his network of scientific connections for future collaborations in the field of nutritional risk assessment.

A Comprehensive In Vivo and In Vitro Assessment of the Drug Interaction Potential of Red Ginseng

Purpose: Red ginseng is one of the world's most popular herbal medicines; it exhibits a wide range of pharmacologic activities and is often co-ingested with other herbal and conventional medicines. This open-label, randomized, 3-period study investigated the in vivo herb–drug interaction potential for red ginseng extract with cytochrome P-450 (CYP) enzymes and organic anion-transporting polypeptide (OATP) 1B1. Methods: Fifteen healthy male volunteers (22-28 years; 57.1-80.8 kg) were administered a single dose of cocktail probe substrates (caffeine 100 mg, losartan 50 mg, omeprazole 20 mg, dextromethorphan 30 mg, midazolam 2 mg, and pitavastatin 2 mg) and single or multiple doses of red ginseng extract for 15 days. Findings: The pharmacokinetic profiles of the probe substrates and metabolites after single- or multiple-dose administration of red ginseng extracts were comparable to the corresponding profiles of the control group. The geometric mean ratio of AUC0–t and 90% CIs for the probe substrate drugs between the control and multiple doses of red ginseng for 15 days were within 0.8 to 1.25 (CYP2C9, CYP3A4, and OATP1B1 probe substrates) or slightly higher (CYP1A2, CYP2C19, and CYP2D6 probe substrates). Additional assessments of the in vitro drug interaction potential of red ginseng extracts and the ginsenoside Rb1 on drug-metabolizing enzymes and transporters using human liver microsomes, cryopreserved human hepatocytes, and transporter-overexpressed cells were negative. Implications: Red ginseng poses minimal risks for clinically relevant CYP- or OATP-mediated drug interactions and is well tolerated. Clinical Research Information Service registry no.:

Concurrent use of prescription drugs and herbal medicinal products in patients with diseases of the musculoskeletal system and connective tissue

Objective The concurrent use of prescription drugs and herbal medicinal products (HMPs) for the management of various disease are increasing. Many HMPs have been used to treat the common health complaints involved the musculoskeletal system and connective tissue. Therefore, we analyzed the extent of concurrent use of prescription drugs and HMPs in patients with diseases of the musculoskeletal system and connective tissue. Methods This study was conducted using the National Health Insurance Service–National Sample Cohort (NHIS-NSC), which consists of representative anonymized data extracted from national health insurance records pertaining to about 1,000,000 subjects from 2002 to 2013. The insured HMPs were 56 kinds of single herbal extracts and 67 kinds of mixed herbal extracts in Republic of Korea. Continuous variables were summarised by the means (and SDs) and categorical variables were summarised by proportions (%). Univariate and multivariable Statistical significance was defined as P Results The diseases of the musculoskeletal system and connective tissue accounted for the top 10 ranking concurrent use of prescription drugs and HMPs. The most frequently co-prescribed drugs were Antipyretics (or Analgesics, or Anti-inflammatory) and Ojeok-san (Wuji-san in China, Goshaku-san in Japan). The concurrent use rate in the elderly over the age of 65 is higher than the sum of all under 64-years-old. Conclusions The concurrent use rate in diseases of the musculoskeletal system and connective tissue was high. Potential herb-drug interaction is a clinical concern, with older people at greater risk. Further studies on the benefit and risk of concurrent use are needed.

Selective Inhibitory Effect of Osthenol on Human Cytochrome 2C8

Osthenol is a furanocoumarin with anti‐tumor, anti‐inflammatory, and anti‐viral activity. It is present in various citrus juices and fruits; however, its inhibitory effects on cytochrome P450 (CYP) enzyme activity, in the context of herb–drug interaction (HDI) prediction, have not been previously studied. In this study, osthenol was chemically synthesized in order to identify potential HDIs. Its inhibitory effect on eight CYP isoforms and the underlying mechanism of inhibition were investigated by using cocktail assays and liquid chromatography‐tandem mass spectrometry in pooled human liver microsomes. The inhibitory effect of osthenol on CYP2C8‐catalyzed paclitaxel hydroxylation was selective and dose‐dependent, but not time‐dependent. The IC50 value was 2.8 μM. Additionally, osthenol displayed mixed mode inhibition with a relatively low Ki value of 0.96 μM, which is indicative of the potential for HDIs with co‐administered CYP2C8 substrates. To the best of our knowledge, this is the first report of selective inhibition of CYP2C8 by osthenol.

Herb-Drug Interactions in Neurological Disorders: A Critical Appraisal.

Herbal drugs are being used worldwide in a variety of debilitating neurological and psychiatric disorders such as cerebrovascular accident, Alzheimer's disease, Parkinson's disease and schizophrenia. However, unlike drugs of modern medicine, herbal drugs are complex products containing multiple pharmacologically active constituents. The nature and relative amounts of these constituents vary due to diverse factors such as but not limited to source of the plant(s), local environmental conditions, parts of the plant used, storage, method of extract preparation, accidental contamination or intentional adulteration. Further, they are handled by the human body like modern drugs and subjected to the processes of absorption, distribution, metabolism and excretion. In each of these processes, they can potentially interact with modern drugs due to sharing of similar transport proteins, metabolizing cytochrome P450 (CYP450) enzymes and uptake / efflux pumps. Moreover, herbal drugs can also inhibit or induce CYP450 enzymes or inactivate transporters leading to Herb-Drug interactions (HDIs). In this narrative review, we have analyzed the clinically reported as well as potential HDIs between 10 common herbal drugs viz. Ginkgo, Ginseng, St. John's Wort, Grapefruit, Black and Long Pepper, Curcumin, Brahmi, Kava, Garlic and Valerian and modern medicines used in neurological and psychiatric disorders with their proven or postulated underlying mechanism(s). Though a number of potential pharmacokinetic and/or pharmacodynamic HDIs have been examined, clinically significant alteration of response to modern medicines and/or serious adverse effects are apparently scarce except for Grapefruit and St. John's Wort. Physicians and patients should exercise caution when using herbal drugs and modern medicines concomitantly so that the recognized serious HDIs can be avoided.

Traditional Chinese medicine: herb-drug interactions with aspirin.

Traditional Chinese medicine (TCM)-based herbal therapies have gained increasing popularity worldwide, raising concerns of its efficacy, safety profile and potential interactions with Western medications. Antithrombotic agents are among the most common prescription drugs involved in herb-drug interactions, and this article focused on aspirin, one of the most widely used antiplatelet agents worldwide. We discussed herbs that have potential interactions by exploring Western and TCM approaches to thrombotic events. Common TCM indications for these herbs were also highlighted, including possible scenarios of their concurrent usage with aspirin. With greater awareness and understanding of potential herb-drug interactions, TCM and Western physicians may collaborate more closely to identify, treat and, most importantly, prevent adverse drug events.

Inhibition of Cytochrome P450 Activities by Extracts of Hyptis verticillata Jacq.: Assessment for Potential HERB-Drug Interactions.

Understanding the potential for adverse drug reactions (ADRs), from herb-drug interactions, is a key aspect of medicinal plant safety, with particular relevance for public health in countries where medicinal plant use is highly prevalent. We undertook an in-depth assessment of extracts of Hyptis verticillata Jacq., via its impact on activities of key cytochrome P450 (CYP) enzymes (CYPs 1A1, 1A2, 1B1, 3A4 and 2D6), its antioxidant properties (determined by DPPH assays) and chemical characterisation (using LC-MS). The dried plant aqueous extract demonstrated potent inhibition of the activities of CYPs 1A1 (7.6 µg/mL), 1A2 (1.9 µg/mL), 1B1 (9.4 µg/mL) and 3A4 (6.8 µg/mL). Further analysis of other crude extracts demonstrated potent inhibition of CYP1A2 activity for a dried plant ethanol extract (1.5 µg/mL), fresh plant ethanol extract (3.9 µg/mL), and moderate activity for a fresh plant aqueous extract (27.8 µg/mL). All four extracts demonstrated strong antioxidant activity, compared to the positive control (ascorbic acid, 1.3 µg/mL), with the dried plant ethanol extract being the most potent (1.6 µg/mL). Analysis of the dried plant aqueous extract confirmed the identity of seven phytochemicals, five lignans and two triterpenes. Individual screening of these phytochemicals against the activity of CYP1A2 identified yatein as a moderate inhibitor (71.9 μM), likely to contribute to the plant extract’s potent bioactivity. Further analysis on the impact of this plant on key drug metabolizing enzymes in vivo appears warranted for likely ADRs, as well as furthering development as a potential chemopreventive agent.

Inhibitory Effect of Sauchinone on UDP-Glucuronosyltransferase (UGT) 2B7 Activity

Herb–drug interaction (HDI) limits clinical application of herbs and drugs, and inhibition of herbs towards uridine diphosphate (UDP)-glucuronosyltransferases (UGTs) has gained attention as one of the important reasons to cause HDIs. Sauchinone, an active lignan isolated from aerial parts of Saururus chinensis (Saururacease), possesses anti-oxidant, anti-inflammatory, and anti-viral activities. In pharmacokinetics of sauchinone, sauchinone is highly distributed to the liver, forming extensive metabolites of sauchinone via UGTs in the liver. Thus, we investigated whether sauchinone inhibited UGTs to explore potential of sauchinone–drug interactions. In human liver microsomes (HLMs), sauchinone inhibited activities of UGT1A1, 1A3, 1A6, and 2B7 with IC50 values of 8.83, 43.9, 0.758, and 0.279 μM, respectively. Sauchinone also noncompetitively inhibited UGT1A6 and 2B7 with Ki values of 1.08 and 0.524 μM, respectively. In in vivo interaction study using mice, sauchinone inhibited UGT2B7-mediated zidovudine metabolism, resulting in increased systemic exposure of zidovudine when sauchinone and zidovudine were co-administered together. Our results indicated that there is potential HDI between sauchinone and drugs undergoing UGT2B7-mediated metabolism, possibly contributing to the safe use of sauchinone and drug combinations.

Aspalathin from Rooibos (Aspalathus linearis): A Bioactive C-glucosyl Dihydrochalcone with Potential to Target the Metabolic Syndrome.

Aspalathin is a C-glucosyl dihydrochalcone that is abundantly present in Aspalathus linearis. This endemic South African plant, belonging to the Cape Floristic region, is normally used for production of rooibos, a herbal tea. Aspalathin was valued initially only as precursor in the formation of the characteristic red-brown colour of "fermented" rooibos, but the hype about the potential role of natural antioxidants to alleviate oxidative stress, shifted interest in aspalathin to its antioxidant properties and subsequently, its potential role to improve metabolic syndrome, a disease condition interrelated with oxidative stress. The potential use of aspalathin or aspalathin-rich rooibos extracts as a condition-specific nutraceutical is hampered by the limited supply of green rooibos (i.e., "unfermented" plant material) and low levels in "fermented" rooibos, providing incentive for its synthesis. In vitro and in vivo studies relating to the metabolic activity of aspalathin are discussed and cellular mechanisms by which aspalathin improves glucose and lipid metabolism are proposed. Other aspects covered in this review, which are relevant in view of the potential use of aspalathin as an adjunctive therapy, include its poor stability and bioavailability, as well as potential adverse herb-drug interactions, in particular interference with the metabolism of certain commonly prescribed chronic medications for hyperglycaemia and dyslipidaemia.

Effects of diclofenac on the pharmacokinetics of celastrol in rats and its transport

Context: Diclofenac and celastrol are always used together for the treatment of rheumatoid arthritis; the herb–drug interaction potential between diclofenac and celastrol is still unknown.Objective: This study investigates the effects of diclofenac on the pharmacokinetics of celastrol in rats.Materials and methods: Twelve male Sprague-Dawley rats were divided into two groups and received celastrol (1 mg/kg) or both celastrol (1 mg/kg) and diclofenac (10 mg/kg) by oral gavage, and blood samples were collected via the oculi chorioideae vein and determined using the LC-MS method developed in this study. Additionally, the effects of diclofenac on the transport of celastrol were investigated using a Caco-2 cell transwell model.Results: Diclofenac could significantly (p < 0.05) decrease the Cmax (from 66.93 ± 10.28 to 41.25 ± 8.06 ng/mL) and AUC0-t (from 765.84 ± 163.61 to 451.33 ± 110.88 μg × h/L) of celastrol in rats. The efflux ratio of celastrol increased significantly (p < 0.05) from 3.12 to 4.55 with the treatment of diclofenac.Discussion and conclusion: These results indicated that diclofenac could decrease the system exposure of celastrol in rats when they are co-administered, and these effects might be exerted via decreasing its absorption in intestine.

Effects of psoralen on the pharmacokinetics of anastrozole in rats

Context: Psoralen and anastrozole are always used together for breast cancer patients in Chinese clinics.Objective: This study investigates the effects of psoralen on the pharmacokinetics of anastrozole in rats and its potential mechanism.Materials and methods: The pharmacokinetics of orally administered anastrozole (0.5 mg/kg) with (test group) or without (Control group) psoralen pretreatment (20 mg/kg/day for 10 days) in male Sprague-Dawley rats (six rats in each group) were investigated. The plasma concentration of anastrozole was determined using a sensitive and reliable LC-MS/MS method. Additionally, the effects of psoralen on the intestine transport and metabolic stability of anastrozole (1 μM) were investigated using a Caco-2 cell transwell model and rat liver microsome incubation systems.Results: The results indicated that psoralen could significantly increase the Cmax (from 56.74 ± 3.17 ng/mL to 83.26 ± 6.87 ng/mL), and t1/2 (from 10.80 ± 1.05 to 14.29 ± 1.38 h) of anastrozole (p < 0.05). Psoralen could also significantly decrease the efflux ratio of anastrozole from 1.88 to 1.32 (p < 0.05). Additionally, the intrinsic clearance rates of anastrozole decreased significantly (from 62.83 to 43.97 μL/min/mg protein) (p < 0.05) with psoralen pretreatment in rat liver microsome incubation systems.Discussion and conclusions: This study indicates that when the rats were pretreated with psoralen, the system exposure of anastrozole would be increased significantly. The results showed that the herb-drug interaction between psoralen and anastrozole might occur when they were co-administered, and future studies in humans also need to investigate its herb-drug interaction potential.

Drug Interaction Potential of Tinospora cordifolia: A Review

Natural products mainly herbs are regularly administered in combination with conventional drugs, hoisting the potential of herb-drug interactions. When the constituents of herb regulate absorption, distribution, metabolism, and excretion of other co-administered drugs, then there will be an onset of pharmacokinetic drug interaction. On the other hand when the constituents alter the activity of receptors involved in the mechanism of action of the co-administered drug, then there will be an onset of a pharmacodynamic interaction. Tinospora cordifolia (TC) is widely used in Ayurvedic medicine as a tonic vitalizer, antipyretic and as a remedy for diabetes and other metabolic disorders. Hence TC is considered as a Complementary and Alternative Medicine (CAM) in the form of herbal supplement. Overall it is observed that people suffering from various diseases are using herbal medicines in the form of a single herb or a polyherbal preparation, besides the prescribed medicines. These herbal formulations are considered to function as a nutritive supplement. Even though herbal supplements are claimed to be free from side effects but needs to be assessed for the HDI potential with the co-administered prescription drug. Hence, an intense effort has been made here to review and analyze the affirmative as well as negative impact of TC with commonly co-administered contemporary medicine.

In vitro modulation of the cytochrome P450 and ABCB1/P-glycoprotein activities of the aqueous extract of Allophylus cominia (L) Sw. leaves.

The aqueous extract of the Allophylus cominia (L) Sw (Sapindaceae) leaves has shown anti-diabetic, anti-obesity and anti-inflammatory properties. In the Caribbean region, it is typically used for the treatment of type-2 diabetes. Considering the herb-drug interaction, the aim of this study was to evaluate the potential effects of the A. cominia extract on the cytochrome P450 (CYP) (rat hepatocyte model) and P-glycoprotein (P-gp) (4T1 cell line) systems. The extract did not decrease the cell viability after being assayed by the MTT test at up to 1500 μg/mL for 72 h. The exposure of the cultured rat hepatocytes to the product (up to 250 μg/mL) for 48 h increased the activities of CYP-1A2, 2C9, and 2E1 by 1.46-, 1.60-, and 1.51-fold, respectively, compared with the controls. The activities of CYP-2B6, 2D6, and 3A4 were not significantly altered, whereas the activity of P-gp decreased by 2- and 4-fold. In addition, the extracts at 100 and 200 μg/mL significantly increased doxorubicin cytotoxicity in these cells 24 h after treatment. The findings indicate that the A. cominia extract modulates the CYP and P-gp systems increasing sensitivity to doxorubicin. Further studies are necessary to evaluate the potential herb-drug interaction or chemosensitive properties.

Effects of mistletoe products on pharmacokinetic drug turnover by inhibition and induction of cytochrome P450 activities

BackgroundEuropean mistletoe (Viscum album) products used in cancer therapy are frequently combined with other anti-cancer-drugs. Hence, potential herb-drug interactions have become a major safety concern in mistletoe therapy.MethodsThree European mistletoe products (Helixor® A, Helixor® M and Helixor® P from mistletoe grown on firs, apple trees and pines, respectively) were tested for inhibition of nine major cytochrome P450 (CYP) isoenzymes in a test system using pooled human liver microsomes and for induction of five CYP isoforms in human hepatocytes cultivated in vitro according to the relevant guideline.ResultsMajor inhibition did not occur in any of the CYP marker reactions. For some CYP isoenzymes, a minor or intermediate inhibition could be observed, but without dose effect relationship. Induction activity (≥ 1.5-fold increase) was not found with any of the three mistletoe products.ConclusionSince no induction capacity was found and major inhibition above 50% did not occur even with the highest concentration used, which is approximately 100,000-fold higher than the clinically relevant dose in plasma, a clinically relevant herb-drug interaction is not expected for Helixor® A, M, and P.

Pregnancy, prescription medicines and the potential risk of herb-drug interactions: a cross-sectional survey

BackgroundPregnant women are routinely prescribed medicines while self-medicating with herbal natural products to treat predominantly pregnancy related conditions. The aim of this study was to assess the potential for herb-drug interactions (HDIs) in pregnant women and to explore possible herb-drug interactions and their potential clinical significance.MethodsA cross-sectional survey of women during early pregnancy or immediately postpartum in North-East Scotland. Outcome measures included; Prescription medicines use excluding vitamins and potential HDIs assessed using Natural Medicines Comprehensive Database.ResultsThe survey was completed by 889 respondents (73% response rate). 45.3% (403) reported the use of at least one prescription medicine, excluding vitamins. Of those taking prescription medicines, 44.9% (181) also reported concurrent use of at least one HNP (Range 1–12). A total of 91 different prescription medicines were reported by respondents using HNPs. Of those taking prescription medicines, 44.9% (181) also reported concurrent use of at least one HNP (Range 1–12). Thirty-four herb-drug interactions were identified in 23 (12.7%) women with the potential to increase the risk of postpartum haemorrhage, alter maternal haemodynamics, and enhance maternal/fetal CNS depression.Almost all were rated as moderate (93.9%), one as a potentially major (ginger and nifedipine) and only one minor (ondansetron and chamomile).ConclusionAlmost half of pregnant women in this study were prescribed medicines excluding vitamins and minerals and almost half of these used HNPs. Potential moderate to severe HDIs were identified in an eighth of the study cohort. Healthcare professionals should be aware that the concurrent use of HNPs and prescription medicines during pregnancy is common and carries potential risks.

Modulation of Cytochrome P450, P-glycoprotein and Pregnane X Receptor by Selected Antimalarial Herbs-Implication for Herb-Drug Interaction.

Seven medicinal plants popularly used for treating malaria in West Africa were selected to assess herb-drug interaction potential through a series of in vitro methods. Fluorescent cytochrome P450 (CYP) assays were conducted using the recombinant CYP enzymes for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 to assess the effect of the methanolic extracts on the metabolic activity of CYPs. Secondly, the inhibitory effect of the extracts was evaluated on P-glycoproteins (P-gp) using calcein-AM, a fluorescent substrate, in MDCK-II and hMDR1-MDCK-II cells. The inhibition of P-gp activity was determined as a reflection of increase in calcein-AM uptake. Additionally, the enzyme induction potential of the extracts was assessed through the modulation of PXR activity in HepG2 cells transiently transfected with pSG5-PXR and PCR5 plasmid DNA. Significant inhibition of CYP activity (IC50 < 10 µg/mL) was observed with the following herbs: A. muricata [CYP2C9, 3A4 and CYP2D6]; M. indica [CYP2C9]; M. charantia [CYP2C9 and CYP2C19]; P. amarus [CYP2C19, CYP2C9 and CYP3A4]; T. diversifolia [CYP2C19 and CYP3A4]. Extracts of four herbs (P. amarus, M. charantia, T. diversifolia and A. muricata) exhibited significant inhibition of P-gp with IC50 values (µg/mL) of 17 ± 1, 16 ± 0.4, 26 ± 1, and 24 ± 1, respectively. In addition, four herbs (A. mexicana, M. charantia, P. amarus and T. diversifolia) showed a >two-fold increase in induction in PXR activity. These findings suggest that these herbs may be capable of eliciting herb-drug interactions if consumed in high quantities with concomitant use of conventional therapies.