Dill Shows Potential for Herb-Drug Interactions via Up-Regulation of CYP1A2, CYP2C19, SULT1A1, NAT2 and ABCB1 in Caco-2 Cells.

<b>Background and Objective:</b> Dill<i> </i>(<i>Anethum graveolens</i> L.) has the potential to develop as a new alternative medicine due to its pharmacological activities. However, studies into its safety regarding herb-drug interactions have been neglected. This study investigated the risk of dill-induced herb-drug interactions (HDI) by examining its effect on the expression of phase I and II drug-metabolizing enzyme and transporter genes in Caco-2 cells. <b>Materials and Methods:</b> Caco-2 cells (5×10⁵ cells/well) were treated with 10 µM ketoconazole, 20 µM rifampicin or dill extract (60-240 µg mL¹) for 72 hrs. Cell viability was assessed using the resazurin assay and reactive oxygen species (ROS) content was determined with 2 ,7 -dichlorofluorescein diacetate. Aspartate (AST) and alanine aminotransferase (ALT) levels were measured using L-aspartate and L-alanine with α-ketoglutarate as substrate. Expression of phase I (<i>CYP1A2</i>, <i>CYP2C19</i>, <i>CYP2D6</i>, <i>CYP2E1 </i>and <i>CYP3A4</i>) and II (<i>UGT1A6</i>,<i> SULT1A1</i>,<i> NAT1</i>,<i> NAT2 </i>and<i> GSTA1/2</i>) metabolizing genes and transporters (<i>ABCB1</i>,<i> ABCC2</i>,<i> ABCG2 </i>and <i>SLCO1B1</i>) were determined by RT/qPCR. <b>Results:</b> All tested concentrations of dill did not affect cell viability or AST and ALT levels. The highest concentration of dill extract (240 µg mL¹) significantly lowered the ROS level. Expression of <i>CYP1A2</i>, <i>CYP2C19</i>, <i>SULT1A1</i>, <i>NAT2 </i>and <i>ABCB1 </i>mRNA was significantly up-regulated by dill extract. <b>Conclusion:</b> Dill extract did not directly damage Caco-2 cells but prolonged use of dill may increase the risk of HDI via the up-regulation of the drug-metabolizing genes <i>CYP1A2</i>, <i>CYP2C19</i>, <i>SULT1A1</i>, <i>NAT2 </i>and the transporter <i>ABCB1</i>.

The dietary supplement of Ginkgo biloba: a comprehensive review of its potential interactions based on pre-clinical and clinical evidences / El suplemento dietético de Ginkgo biloba: una revisión exhaustiva de sus posibles interacciones basada en evidencias clínicas y preclínicas

This review present Gingko biloba (GB) interactions, based on clinical and pre-clinical presentations. Literature was retrieved using databases; ScienceDirect, PubMed, Google scholar, Web of Science, Scopus etc. 14/45 interactions were found with clinical presentations. More interactions (80%) were reported with drugs followed by herbs (11.1%), and nutraceuticals (6.7%) with major mechanisms of interaction observed as; inhibition of Cytochrome metabolizing enzymes (44.4%) and platelet-activating factor (PAF) i.e. 15.6%. Major clinical features were; increased bleeding (eye, parietal), hematomas (subdural), and seizures as well as increased blood pressure, priapism, loss of infection/antiviral failure, and coma. Drugs with major interactions belonged to anti-platelet/anti-coagulant and NSAIDs. Synergistic effects were observed for GB vs herbs (except cannabis which showed rhabdomyolysis), foods, and nutraceuticals (except pyridoxine where neurotoxicity was seen). GB use should be monitored and the patient may seek proper advice from a healthcare professional.

Esta revisión presenta las interacciones de Gingko biloba (GB), basadas en presentaciones clínicas y preclínicas. La literatura se recuperó utilizando bases de datos; ScienceDirect, PubMed, Google Scholar, Web of Science, Scopus, etc. Se encontraron 14/45 interacciones con presentaciones clínicas. Se informaron más interacciones (80%) con fármacos seguidos de hierbas (11,1%) y nutracéuticos (6,7%) con los principales mecanismos de interacción observados como; inhibición de las enzimas metabolizadoras del citocromo (44,4%) y factor activador de plaquetas (PAF), es decir, 15,6%. Las principales características clínicas fueron; aumento de sangrado (ojo, parietal), hematomas (subdural) y convulsiones, así como aumento de la presión arterial, priapismo, pérdida de infección / insuficiencia antiviral y coma. Los fármacos con interacciones importantes pertenecían a los antiplaquetarios/anticoagulantes y los AINE. Se observaron efectos sinérgicos para GB frente a hierbas (excepto cannabis que mostró rabdomiólisis), alimentos y nutracéuticos (excepto piridoxina donde se observó neurotoxicidad). Se debe controlar el uso de GB y el paciente puede buscar el asesoramiento adecuado de un profesional de la salud.

Water extract of Er-xian decoction selectively exerts estrogenic activities and interacts with SERMs in estrogen-sensitive tissues.

ETHNOPHARMACOLOGICAL RELEVANCE: The increasing use of "kidney"-nourishing Traditional Chinese Medicine (TCM) like Er-xian decoction (EXD) for management of menopausal symptoms and osteoporosis has aroused concerns about their safety, and whether they interact with prescription drugs as both of them act via estrogen receptors (ERs) and regulate serum estradiol. AIM OF THE STUDY: The present study aimed to evaluate whether EXD selectively exerted estrogenic activities and interacted with Selective Estrogen Receptor Modulators (SERMs). MATERIALS AND METHODS: In vivo, mature ovariectomized (OVX) rats were administrated with EXD or combined treatment of EXD and SERMs for 12 weeks. The tissue-selective effect of EXD and its interaction of SERMs were studied in four estrogen sensitive tissues, bone, brain, breast and uterus. In vitro, the interaction of extracts of EXD-treated serum and SERMs in four ER-positive cell lines. RESULTS: In OVX rats, EXD selectively alleviated estrogen deficiency-induced changes in the bone and brain without inducing any estrogenic effects in the breast or uterus. Two-way ANOVA indicated the presence of interactions between EXD and SERMs in OVX rats but EXD did not significantly alter the tissue responses to SERMs in the bone, breast or brain. Indeed, the combined use of EXD and SERMs appeared to suppress the estrogenic effect of raloxifene and tamoxifen in the uterus. Extract of EXD-treated serum directly stimulated cell proliferation or differentiation in human osteosarcoma MG-63, neuroblastoma SHSY5Y, breast cancer MCF-7, and endometrial Ishikawa cells. Two-way ANOVA revealed that EXD-treated serum interacted with SERMs at various concentrations and altered the effects of tamoxifen in MG-63 and MCF-7 cells. CONCLUSIONS: EXD exerted estrogenic effects in a tissue-selective manner and interacted with SERMs. Combined treatment of EXD and SERMs did not hamper the beneficial effects of SERMs on the bone or brain but appeared to moderate the estrogenic effect of SERMs in the uterus.

Drug-herb interactions between Scutellaria baicalensis and pharmaceutical drugs: Insights from experimental studies, mechanistic actions to clinical applications.

Whilst the popular use of herbal medicine globally, it poses challenges in managing potential drug-herb interaction. There are two folds of the drug-herb interaction, a beneficial interaction that may improve therapeutic outcome and minimise the toxicity of drug desirably; by contrast, negative interaction may evoke unwanted clinical consequences, especially with drugs of narrow therapeutic index. Scutellaria baicalensis Georgi is one of the most popular medicinal plants used in Asian countries. It has been widely used for treating various diseases and conditions such as cancer, diabetes, inflammation, and oxidative stress. Studies on its extract and bioactive compounds have shown pharmacodynamic and pharmacokinetic interactions with a wide range of pharmaceutical drugs as evidenced by plenty of in vitro, in vivo and clinical studies. Notably, S. baicalensis and its bioactives including baicalein, baicalin and wogonin exhibited synergistic interactions with many pharmaceutical drugs to enhance their efficacy, reduce toxicity or overcome drug resistance to combat complex diseases such as cancer, diabetes and infectious diseases. On the other hand, S. baicalensis and its bioactives also affected the pharmacokinetic profile of many drugs in absorption, distribution, metabolism and elimination via the regulatory actions of the efflux pumps and cytochrome P450 enzymes. This review provides comprehensive references of the observed pharmacodynamic and pharmacokinetic drug interactions of Scutellaria baicalensis and its bioactives. We have elucidated the interaction with detailed mechanistic actions, identified the knowledge gaps for future research and potential clinical implications. Such knowledge is important for the practice of both conventional and complementary medicines, and it is essential to ensure the safe use of related herbal medicines. The review may be of great interest to practitioners, consumers, clinicians who require comprehensive information on the possible drug interactions with S. baicalensis and its bioactives.

The effect of grape seed and green tea extracts on the pharmacokinetics of imatinib and its main metabolite, N-desmethyl imatinib, in rats.

BACKGROUND: Imatinib is mainly metabolized by CYP3A4 and to a lesser extent by other isoenzymes, with N-desmethyl imatinib being its major equipotent metabolite. Being a CYP3A4 substrate, imatinib co-administration with CYP3A4 modulators would change its pharmacokinetic profile. The cancer chemoprevention potential and anticancer efficacy of many herbal products such as grape seed (GS) and green tea (GT) extracts had led to an increase in their concomitant use with anticancer agents. GS and GT extracts were demonstrated to be potent inhibitors of CYP3A4. The aim of this study is to investigate the effect of standardized GS and/or GT extracts at two different doses on the pharmacokinetics of imatinib and its metabolite, N-desmethyl imatinib, in SD-rats. METHODS: Standardized GS and/or GT extracts were administered orally once daily for 21 days, at low (l) and high (h) doses, 50 and 100 mg/kg, respectively, before the administration of a single intragastric dose of imatinib. Plasma samples were collected and analyzed for imatinib and N-desmethyl imatinib concentrations using LC-MS/MS method, then their non-compartmental pharmacokinetic parameters were determined. RESULTS: h-GS dose significantly decreased imatinib's Cmax and the [Formula: see text] by 61.1 and 72.2%, respectively. Similar effects on N-desmethyl imatinib's exposure were observed as well, in addition to a significant increase in its clearance by 3.7-fold. l-GT caused a significant decrease in imatinib's Cmax and [Formula: see text] by 53.6 and 63.5%, respectively, with more significant effects on N-desmethyl imatinib's exposure, which exhibited a significant decrease by 79.2 and 81.1%, respectively. h-GT showed similar effects as those of l-GT on the kinetics of imatinib and its metabolite. However, when these extracts were co-administered at low doses, no significant effects were shown on the pharmacokinetics of imatinib and its metabolite. Nevertheless, increasing the dose caused a significant decrease in Cmax of N-desmethyl imatinib by 71.5%. CONCLUSIONS: These results demonstrated that the pharmacokinetics of imatinib and N-desmethyl imatinib had been significantly affected by GS and/or GT extracts, which could be partially explained by the inhibition of CYP3A-mediated metabolism. However, the involvement of other kinetic pathways such as other isoenzymes, efflux and uptake transporters could be involved and should be characterized.

Co-administration of Wuzhi tablet (Schisandra sphenanthera extract) alters tacrolimus pharmacokinetics in a dose- and time-dependent manner in rats.

ETHNOPHARMACOLOGY RELEVANCE: Tacrolimus is a well-known potent but expensive immunosuppressant. We previously clarified the herb-drug interaction between tacrolimus and Wuzhi tablet (WZ), a prescribed drug of ethanol extract of Schisandra sphenanthera, and showed the ideal effect of WZ on maintaining therapeutic level of tacrolimus and reducing the total drug expense. However, WZ possesses a biphasic effect on regulating CYP3A (the major metabolizing enzyme of tacrolimus), which could induce the mRNA and protein expression after long-term treatment while transiently inhibit the activity of CYP3A. In clinic, clinicians are confused about the relationship between the blood concentration of tacrolimus and the dose and the duration of pretreatment of WZ. Therefore, the effects of the pretreatment time and the dose of WZ on the pharmacokinetics of tacrolimus is urgently needed to be clarified to better combine the use of WZ and tacrolimus in clinic. AIM OF THE STUDY AND METHOD: This study aimed to investigate the effects of the pretreatment time and the dose of WZ on the pharmacokinetics of tacrolimus in rats. RESULTS AND CONCLUSIONS: After pretreated rats with WZ for 0, 0.5, 2, 6, 12 or 24 h, the area under the curve (AUC) of tacrolimus was 2.27 ± 0.59, 1.87 ± 1.14, 2.86 ± 0.64, 1.62 ± 0.70, 1.54 ± 1.06 and 1.12 ± 0.69-fold of that of the tacrolimus alone group, respectively. The ratio of AUC of tacrolimus to that of the co-administration group with 0, 62.5, 125, 250, 500 or 750 mg/kg of WZ was 1.00: 1.07: 1.44: 2.60: 2.32: 2.42, respectively. These findings suggested that WZ increased tacrolimus AUC in a pretreatment time- and dose-dependent manner. In line with the in vivo findings, WZ extract inhibited CYP3A activity in a pre-treatment time- and concentration-dependent manner in human liver microsomes. In conclusion, the pharmacokinetics of tacrolimus was significantly affected by the pretreatment time and the dose of WZ. Oral pretreatment with WZ for 0-2 h or co-dosing of 250 mg/kg of WZ most significantly increased the blood concentration of tacrolimus. These findings would be helpful for guiding the reasonable use of WZ and tacrolimus in clinic.

Is it safe to take Radix Salvia Miltiorrhiza - Radix Pueraria Lobate product with warfarin and aspirin? A pilot study in healthy human subjects.

ETHNOPHARMACOLOGICAL RELEVANCE: Radix Salvia Miltiorrhiza (Danshen) and Radix Pueraria Lobate (Gegen) are officially listed in the Chinese Pharmacopoeia and have long been used together as a Compound Chinese Traditional Medicine (CCTM) for treatment of coronary heart diseases, which are often co-administered with aspirin or warfarin to patients suffering from cardiovascular diseases. AIM OF STUDY: Since significant pharmacokinetic and pharmacodynamic interactions between Danshen-Gegen (DG) formula and aspirin/warfarin have been observed in our previous rat studies, the current study was proposed aiming to further verify such pharmacokinetic and pharmacodynamic interactions in healthy human subjects and explore related mechanisms. MATERIALS AND METHODS: A 5-day, multiple dose, five-session clinical trial has been carried out (n = 14) with 2-week washout periods between sessions, during which the subjects would receive different combinations of the medications. Plasma samples were collected for pharmacokinetic evaluation, and whole blood samples were collected for pharmacodynamic evaluation. In addition, an in-vitro mechanistic study is conducted to investigate the role of danshensu on the anti-thrombotic and anti-platelet aggregation effects of warfarin and aspirin respectively. RESULTS: Significant pharmacokinetic and pharmacodynamic herb-drug interactions were observed in healthy human subjects. pharmacokinetically, co-administration of DG with aspirin or warfarin could lead to a moderately increased AUC0→t of aspirin and a decreased AUC0→t of 7-hydroxyl warfarin respectively. The systemic exposure of danshensu (DSS, the marker component of DG) would be significantly increased after co-administration with warfarin. Pharmacodynamically, a reduction in systemic thromboxane B2 concentration was noticed after administration of DG with aspirin, which could be associated with the increased systemic exposure of aspirin and the synergistic effect of danshensu, aspirin and salicylic acid on cyclooxygenase (COX) inhibition. An offset on the warfarin induced soluble thrombomodulin induction was observed after its co-administration with DG, which could be partially attributed to the COX-2 inhibition effect of danshensu. CONCLUSION: Our results indicated that co-administration of DG with aspirin/warfarin would lead to significant pharmacokinetic and pharmacodynamic herb-drug interactions in healthy human subjects.

Herb-drug interaction of gastrodiae rhizoma on carbamazepine: A pharmacokinetic study in rats.

OBJECTIVE: Gastrodiae Rhizoma (GR), is a traditional Chinese Medicine that has been used for neurological disorders, including epilepsy. Epilepsy patients may be treated with adjunctive therapy of GR with antiepileptic drugs (AEDs). In particular, carbamazepine (CBZ) is of high potential to interact with concurrent treatment of Chinese Medicine. This study was to investigate the herb-drug interactions of GR and CBZ, an AED, through pharmacokinetic approach in rats. METHODS: We adopted a high-performance liquid chromatography (HPLC) system to quantify the plasma level of CBZ and its metabolite (carbamazepine-10, 11-epoxide, CBZE). The method was validated as per instructions under United States Food and Drug Administration (USFDA) guidance. For the herb-drug interaction study, rats were randomly divided into four different treatment groups: single-dose CBZ treatment, single-dose CBZ/GR treatment, 2-week course of CBZ treatment and 2-week course of CBZ/GR treatment. RESULTS: Our results demonstrated the auto-induction of CBZ metabolization when comparing single-dose with 2-week course of CBZ treatment. Pharmacokinetic interactions were noted in concomitant use of GR with CBZ by comparing two single-dose treatments (CBZ versus CBZ/GR). Our data showed that GR increased the mean residence time (MRT0-t) and the time taken to reach the maximum concentration (Tmax) of CBZ in single-dose of CBZ/GR treatment. The maximum drug concentration (Cmax) of CBZ was reduced in single-dose CBZ/GR treatment. When comparing the 2-week course of CBZ treatment with the 2-week course of CBZ/GR treatment, the MRT0-t and half-life of CBZ were increased. The AUC0-t, the Cmax and the half-life of CBZE were increased. CONCLUSION: CBZ/GR treatment may reduce the auto-induction of CBZ over 2 weeks. While the reduction of auto-induction could enhance the therapeutic effects of CBZ, it could also lead to an increase in neurological side effects and non-neurological adverse effects. Our results provided preclinical evidence of herb-drug interaction, which may have implications for epilepsy patients treated with GR.

Herbal supplements interactions with oral oestrogen-based contraceptive metabolism and transport.

The increased use of herbal supplements as complementary or alternative medicines has become a clinical conundrum due to the potential for herb-drug interactions. This is exacerbated by an increased supply of new herbal supplements in the market claiming various health advantages. These herbal supplements are available as over-the-counter self-medications. Herbal supplements are generally perceived as efficacious without side effects commonly associated with conventional drugs. However, despite regulations, claims related to their therapeutic effects are mostly unsupported by scientific evidence. These products often lack suitable product quality controls, labelled inadequately and with batch to batch variations, potentially compromising the safety of the consumer. Amongst health practitioners, the greatest concern is related to the lack of chemical characterization of the active compounds of the herbal supplements. The interaction between these different active components and their concomitant effects on other conventional drugs is generally not known. This review will focus on herbal supplements with the potential to effect pharmacokinetic and pharmacodynamic properties of oestrogen-based oral contraceptives. The use of herbal supplements for weight management, depression, and immune boosting benefits were selected as likely herbal supplements to be used concomitantly by women on oral contraceptives.

Herb-drug interaction studies of herbs used in treatment of cardiovascular disorders-A narrative review of preclinical and clinical studies.

About 70% of the world population is currently using medicinal herbs as complementary or alternative medicine, which is increasing at a tremendous pace in both developed and developing countries in the last two decades (World Health Organization Medicines Strategy 2002-2005). This increase in consumer demand of medicinal herbs continues despite the rarity of scientific data to establish their safety and efficacy profile. Its popularity is also attributed to several factors, including easy availability, cost effectiveness leading to better purchasing power and general perception that they are safe. Herbs are often administered concomitantly with therapeutic drugs for the treatment of major ailments, raising the potential for herb-drug interactions (HDIs). The major pathways postulated for HDIs involves the cytochrome P450 (CYP450)-mediated inhibition or induction and transport and efflux proteins. In our review, we highlight frequently used herbal medicines for the treatment of cardiovascular disorders (CVD), their established HDIs studied using in vitro tools and in vivo pharmacokinetic and pharmacodynamic assays and case reports. Herbs have been divided into different sections on the basis of availability of HDI data in relevance to cardiovascular drugs: herbs reported to interact with cardiac drugs, herbs yet to be reported for interaction with drugs of any class and herbs reported to interact with drugs of other therapeutic category but not with cardiac drugs. The amount of active phytoconstituents present in the selected herbs and their extent of bioavailability are also mentioned. This review can serve as a quick reference database for physicians and health care professionals involved in CVD treatment, aimed at maximizing clinical outcomes with reduction in adverse and toxic effects.

A study to evaluate herb-drug interaction underlying mechanisms: An investigation of ginsenosides attenuating the effect of warfarin on cardiovascular diseases.

Warfarin and ginseng have been widely used in the treatment of cardiovascular diseases. However, the clinical safety and effectiveness of herb-drug combination treatment are still controversial. Therefore, it is very essential to probe the interaction between warfarin and ginseng. In this study, in vitro and in vivo study was carried out to demonstrate that whether there is an interaction between warfarin and ginsenosides (GS), which is the main component of ginseng. In vitro study showed that the adhesion ability between endothelial cells and matrigel/platelets was enhanced due to the up-regulating expression of intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) proteins by treatment of warfarin+GS combination compared to warfarin/GS treatment alone. Moreover, GS could weaken the anticoagulation effect of warfarin in hyperlipemia rats owning to the increased expression levels of coagulation factors and hepatic cytochrome P450 enzymes in plasma after long-term co-administration of warfarin with GS. The results of both in vitro and in vivo study demonstrated that there is a serious interaction between warfarin and ginseng, which may deteriorate atherosclerosis and thrombosis after combined use of warfarin and GS.

Effects of Yukmijihwang-tang, a Polyherb, on the Pharmacokinetics of Metformin.

Metformin is one of the most common medicines for the treatment of type 2 diabetes, however, recent studies suggest that concomitant antihyperglycemic agents should be administered for better efficacy. Yukmijihwang-tang (YMJHT) is a nephroprotective polyherb prescribed for renal disorders or diabetic mellitus in traditional Korean medicine. Therefore, the pharmacokinetics between metformin and YMJHT were examined for their coadministration. Rats were orally coadministered with metformin and YMJHT as a combination group or metformin and distilled water as the corresponding control. Then, the metformin concentration in plasma and its pharmacokinetic parameters including maximum concentration (Cmax) and area under the plasma concentration time curve (AUC) were analyzed. There were no interactions between metformin and YMJHT in the single coadministration at intervals within 5 min. However, pretreatments with YMJHT for 6 days increased the metformin concentration and its Cmax and AUC (p<0.05). The repeated coadministration for 8 days increased the Cmax of metformin (p<0.05). Conversely, when the combination was coadministered at 2h -intervals, there were no interactions between metformin and YMJHT after a single dosing or repeated dosing of coadministration for 7 days. These results of the present study will help structure proper dosing regimens for the concomitant therapy of metformin and YMJHT.

Impact of Drug Metabolism/Pharmacokinetics and their Relevance Upon Traditional Medicine-based Cardiovascular Drug Research.

BACKGROUND: The representative cardiovascular herbs, i.e. Panax, Ligusticum, Carthamus, and Pueraria plants, are traditionally and globally used in the prevention and treatment of various cardiovascular diseases. Modern phytochemical studies have found many medicinal compounds from these plants, and their unique pharmacological activities are being revealed. However, there are few reviews that systematically summarize the current trends of Drug Metabolism/Pharmacokinetic (DMPK) investigations of cardiovascular herbs. METHODS: Here, the latest understanding, as well as the knowledge gaps of the DMPK issues in drug development and clinical usage of cardiovascular herbal compounds, was highlighted. RESULTS: The complicated herb-herb interactions of cardiovascular Traditional Chinese Medicine (TCM) herb pair/formula significantly impact the PK/pharmacodynamic performance of compounds thereof, which may inspire researchers to develop a novel herbal formula for the optimized outcome of different cardiovascular diseases. While the Absorption, Distribution, Metabolism, Excretion and Toxicity (ADME/T) of some compounds has been deciphered, DMPK studies should be extended to more cardiovascular compounds of different medicinal parts, species (including animals), and formulations, and could be streamlined by versatile omics platforms and computational analyses. CONCLUSION: In the context of systems pharmacology, the DMPK knowledge base is expected to translate bench findings to clinical applications, as well as foster cardiovascular drug discovery and development.

Potential Interactions of Biologically Based Complementary Medicine in Gynecological Oncology.

OBJECTIVE: The aim of this study was to assess the potential risks of interactions between biologically based complementary and alternative medication (BB-CAM) and conventional drugs during systemic therapy in breast and gynecological cancer patients by analyzing the actual CAM-drug combinations from individual patients' records. METHODS: From September 2014 to December 2014 and from February 2017 to May 2017, all patients (n = 717) undergoing systemic therapy at the Gynecologic Oncology Day Care Unit in the Gynecology and Obstetrics Department of the Technical University of Munich, Germany, were asked to participate in a questionnaire about all their medications. To assess the potential risk of CAM-drug interactions (CDIs), we initially utilized the Lexicomp drug interaction database. This assessment was then expanded with a systematic search of other digital databases, such as the National Center for Complementary and Integrative Health, Memorial Sloan Kettering Cancer Center, PubMed, and MEDLINE as well as the Cochrane Library. RESULTS: Among 448 respondents, 74.1% reported using BB-CAM simultaneously with their systemic therapy. The assessment showed 1 patient with a potentially clinically relevant CDI, where the interaction was based on a self-medicated combination of Echinacea and cyclophosphamide. Furthermore, 81 patients (18.1%) were thought to have interactions because of a combination of BB-CAMs and cytochrome P450 3A4-metabolized anticancer drugs. CONCLUSIONS: Our data demonstrated high overall use of BB-CAMs by cancer patients undergoing systemic therapy. The analyses showed only 1 clinically relevant CDI.

Influences of Corydalis decumbens on the Activities of CYP450 Enzymes in Rats with a Cocktail Approach.

Corydalis decumbens, a Traditional Chinese Medicine, has been widely used for the alternative and/or complementary therapy of hypertension, arrhythmias rheumatoid arthritis, sciatica, stroke, hemiplegia, paraplegia, and vascular embolism. The aim of this study was to determinate the potential effects of Corydalis decumbens on the five cytochrome P450 (CYP) enzyme activities (CYP1A2, CYP3A4, CYP2C9, CYP2C19, and CYP2D6) by cocktail approach. To evaluate whether concurrent use of Corydalis decumbens interferes with the effect of several prescription drugs, saline (control group) or Corydalis decumbens (XTW group) were administrated via gavage for 7 successive days. A probe cocktail solution (phenacetin, omeprazole, metoprolol, tolbutamide, and midazolam) was given 24 h after the last dose of saline or Corydalis decumbens. A specific and sensitive UHPLC-MS/MS method was validated for the determination of five substrates and their metabolites in control group and XTW group. Our results indicated that Corydalis decumbens could have inductive effects of CYP2C19 and inhibit the activities of CYP1A2 and CYP3A4. However, Corydalis decumbens had no significant influence on CYP2C9 and CYP2D6. The herb-drug interaction should require more attention by careful monitoring and appropriate drug dosing adjustments to the concurrent use of western medications which were metabolized by CYP1A2, CYP2C19, and CYP3A4 in human-Corydalis decumbens, Cytochrome P450, Cocktail, Pharmacokinetics, herb-drug interactions.

Herb-drug interaction: A case study of effects and involved mechanisms of cisplatin on the pharmacokinetics of ginsenoside Rb1 in tumor-bearing mice.

Ginseng is often prescribed together with cisplatin for treatment of cancer, but the interaction between ginseng and cisplatin is still unknown. This study employed ginsenoside Rb1 (Rb1), one of the major components in ginseng, to explore the effects and involved mechanisms of cisplatin on the pharmacokinetics of ginseng. The effects of cisplatin on the pharmacokinetics of Rb1 and its bioactive metabolites Rd, Rg3, and F2 were investigated by using A549-bearing mice with and without cisplatin intervention. Our data showed that cisplatin could significantly decrease the AUC(0-t) and Cmax of Rd, Rg3, and F2, except Rb1. To evaluate the involved mechanisms, feces and intestinal mucosa were collected to explore the effects of cisplatin on the gut metabolism of Rb1 in vitro; meanwhile, Caco-2 cell model and small intestine histological characters were examined to evaluate the effects of cisplatin on the gut absorptive areas and permeability. The mechanisms involved may be mainly related to the comprehensive contributions of inhibited intestinal bacteria and mucosa metabolisms, narrowed intestinal absorptive area, increased efflux ratio of intestinal absorption and enhanced intestinal permeability. All these findings suggested that the dosage of ginseng traditionally used for health protection should be adjusted when it was prescribed together with cisplatin in the treatment of cancer.

Influence of andrographolide on the pharmacokinetics of warfarin in rats.

CONTEXT: Andrographolide and warfarin are often used together in clinics in China. However, the herb-drug interaction between andrographolide and warfarin is still unknown. OBJECTIVE: This study investigates the herb-drug interaction between andrographolide and warfarin in vivo and in vitro. MATERIALS AND METHODS: A sensitive and reliable LC-MS/MS method was developed for the determination of warfarin in male Sprague-Dawley rats plasma, and then the pharmacokinetics of orally administered warfarin (0.5 mg/kg) with or without andrographolide (30 mg/kg/day for 7 days) pretreatment was investigated. In addition, Sprague-Dawley rat liver microsomes incubation systems were used to support the in vivo pharmacokinetic data and investigate its potential mechanism. RESULTS: The method validation results showed that a sensitive and reliable LC-MS/MS method was developed for the determination of warfarin in rat plasma samples. The pharmacokinetic results indicated that co-administration of andrographolide could increase the systemic exposure of warfarin significantly, including area under the curve (118.92 ± 18.08 vs. 60.58 ± 9.46 µg × h/mL), maximum plasma concentration (3.32 ± 0.41 vs. 2.35 ± 0.25 µg/mL) and t1/2 (22.73 ± 3.28 vs. 14.27 ± 2.67 h). Additionally, the metabolic stability of warfarin increased from 23.5 ± 4.7 to 38.7 ± 6.1 min with the pretreatment of andrographolide, and the difference was significant (p < 0.05). DISCUSSION AND CONCLUSION: In conclusion, andrographolide could increase the systemic exposure of warfarin in rats when andrographolide and warfarin were co-administered, and possibly by slowing down the metabolism of warfarin in rat liver by inhibiting the activity of CYP3A4 or CYP2C9.

Anxiolytic actions of Nardostachys jatamansi via GABA benzodiazepine channel complex mechanism and its biodistribution studies.

Nardostachys jatamansi has profound applications against pharmacological interventions and is categorized as a hypno-sedative drug according to Ayurveda. In the present study probable mechanism of anxiolytic action of Nardostachys jatamansi extract (NJE) was studied using behavioral anxiolytic tests (Elevated plus maze, Open field test, Light dark box test, and Vogel's conflict test) in mice. Mice were treated orally with NJE (250 mg/kg) for 3, 7 and 14 days or diazepam (1 mg/kg) followed by behavioral assessment and estimation of monoamine neurotransmitters, GABA, and antioxidant enzymes. Treatment of mice for 7 days caused an increase in time spent in open arms in elevated plus maze, number of line crossings in open field test, increased time spent in lit compartment of light-dark box test, an increase in number of licks made and shocks accepted in Vogel's conflict test, with results comparable to diazepam and this treatment also caused a significant increase in monoamine neurotransmitters and GABA in brain and tissue antioxidant parameters. Co-treatment of NJE with flumazenil (GABA-benzodiazepine antagonist; 0.5 mg/kg i.p) or picrotoxin (GABAA gated chloride channel blocker; 1 mg/kg i.p) caused a blockage/antagonised anxiolytic actions of NJE by causing a significant reduction in time spent in open arms of elevated plus maze, an decrease in number of line crossing in open field test and also number of shocks and licks accepted in Vogel's conflict test. Further, NJE was radiolabelled with technetium99m at their hydroxyl groups following which purity as well as in vivo and in vitro stability of radiolabelled formulations was evaluated. The blood kinetics and in vivo bio-distribution studies were carried out in rabbits and mice respectively. Labeled formulation was found to be stable in vitro (96 to 93% stability) and in vivo (96 to 92% stability). The labeled compound was cleared rapidly from blood (within 24 h) and accumulated majorly in kidneys (11.65 ± 1.33), liver (6.07 ± 0.94), and blood (4.03 ± 0.63) after 1 h. However, a small amount was observed in brain (0.1 ± 0.02) probably because of its inability to cross blood-brain barrier. These results highlight biodistribution pattern of NJE, and also indicated that a 7-day treatment with NJE produced significant anxiolytic effects in mice and also a significant increase in brain monoamine and GABA neurotransmitter levels and suggests that anxiolytic effects of NJE are primarily and plausibly mediated by activating GABAergic receptor complex.

Moringa oleifera leaf powder alters the pharmacokinetics of amodiaquine in healthy human volunteers.

WHAT IS KNOWN AND OBJECTIVE: Moringa oleifera (MO) Lam (Moringaceae) is commonly used as food supplement and as medicine in most African countries where malaria is also endemic. Therefore, co-administration of MO with antimalarials is a possibility. This study investigated the effects of MO leaves powder on the pharmacokinetics of amodiaquine (AQ) in human subjects. METHODS: Twenty healthy volunteers were recruited for the 3-period study. In the first period, a single dose of AQ tablet (10 mg/kg) was administered orally after an overnight fast. After a 7-day washout period, AQ was co-administered with MO. For the third period, each subject took 3 g MO once daily for 7 days and on the 8th day, MO was co-administered with AQ. The plasma concentrations of amodiaquine and desethylamodiaquine (DEAQ) were simultaneously determined using a validated HPLC method. RESULTS AND DISCUSSION: The results showed a significant decrease (P = .037) in the Cmax of AQ after concurrent administration (CA) with MO, whereas after pretreatment (PT), there was a 32% decrease in the Cmax of AQ. For the metabolite, DEAQ, Cmax increased significantly (P = .006) by 79.36%, and Cmax in PT was significantly higher than (P = .001) that of the CA arm of the study. AUC of DEAQ increased significantly by 40.4% (P = .006) and by 188% (P = .001) after CA and PT, respectively. WHAT IS NEW AND CONCLUSION: The study established pharmacokinetic interaction between AQ and MO when given together or following a long period of ingestion of MO. This may have clinical implications for malaria therapy.