Natural Health Product-Drug Interaction Causality Assessment in Pediatric Adverse Event Reports Associated with Attention-Deficit/Hyperactivity Disorder Medication.

Background: Some pediatric patients with attention-deficit/hyperactivity disorder (ADHD) use natural health products (NHPs) such as herbal remedies. Although herbal remedies are generally considered to be safe when they are used appropriately, they may contain active components that can interact with medications being used concurrently, with potential for NHP-drug interactions leading to adverse events. Objectives: The objectives of this study were (1) to identify adverse event reports (AERs) involving commonly used herbal remedies and ADHD prescription medicines in children and adolescents; (2) to evaluate the quality of collected AERs; and (3) to assess whether NHP-drug interactions can be causally linked to reported adverse events. Methods: We systematically searched the FDAble database (FDAble.com) for herbal remedies commonly used by patients (4-18 years old) also taking ADHD drugs from 1997 to 2015. We assessed the completeness of the AERs and used three causality assessment tools modified for NHPs (Naranjo Adverse Drug Reaction Probability Scale, HORN Drug Interaction Probability Scale, and World Health Organization Uppsala Monitoring Centre Scale). Results: Of the 23 identified AERs involving both an herbal remedy and an ADHD prescription medication, most involved multiple (>3) substances with inadequate detail to assess multiple potential interactions. Following data extraction and evaluation of completeness, five AERs involving only one herbal remedy and one ADHD medication were evaluated for causality. An NHP-drug interaction was assessed to be probable in one case and to be possible in another. Both these reports involved a methylphenidate formulation and St. John's wort. Conclusions: Eighteen of the 23 identified AERs involving both an herbal remedy and an ADHD drug also involved other multiple ingredient products. The reporting quality was poor for the five AERs examined. Further research is needed to study the interaction between St. John's wort and methylphenidate.

Cannabis and Cannabinoids: Kinetics and Interactions.

Cannabis sativa and related products are widely used, but their potential to cause significant clinical interactions remains unclear, particularly for cannabinoid-enriched or otherwise concentrated products. The pharmacokinetics of most cannabis products is not known. Where information is known, there is wide variation. Extrapolation of limited clinical data is complicated by the complexity and variability of cannabis products as well as their delivery through various routes of administration. In vitro evidence shows that the major cannabinoids are substrates for numerous metabolic enzymes, including the cytochrome P450 metabolizing enzymes. Whereas many consumers consider cannabis products to be safe relative to alternative prescription or narcotic drugs, clinical reports of cannabis-related drug interactions and adverse events are increasing in frequency. Patients using these products, whether for medical or nonmedical purposes, together with conventional therapeutic agents may be at increased risk of adverse events, including therapeutic failure, and require enhanced monitoring.

Effect of an anxiolytic botanical containing Souroubea sympetala and Platanus occidentalis on in-vitro diazepam human cytochrome P450-mediated metabolism.

OBJECTIVES: A novel anxiolytic natural health product (NHP) containing Souroubea sympetala and Platanus occidentalis is available for the companion animal market and is currently being developed for clinical evaluation. Addressing the risk of potential NHP-drug interactions, this study investigated S. sympetala and P. occidentalis plant extracts, and their identified bioactive compounds, for effects on the activity of cytochrome P450 (CYP) isozymes and the metabolism of the conventional anti-anxiety medication diazepam. METHODS: Souroubea sympetala and P. occidentalis extracts, a 1 : 1 blend of the two extracts, and five triterpenes were tested for inhibitory effects on human recombinant CYP3A4, CYP2D6, CYP2C9 and CYP2C19 activity using a fluorometric plate assay. Direct effects on the metabolism of diazepam were evaluated using human liver microsomes with drug and metabolite quantification by ultra-high-pressure liquid chromatography and mass spectroscopy. KEY FINDINGS: The active substances betulinic acid (BA) and ursolic acid (UA) strongly inhibited CYP3A4 activity while UA and lupeol moderately inhibited CYP2C19. All extracts exhibited strong activity against the tested isozymes at 50-100 µg/ml. BA and all plant extracts blocked the formation of major diazepam metabolites. CONCLUSIONS: Betulinic acid, UA and both the extracts and blended product are expected to affect the metabolism of diazepam when given in high dose.

In vitro activity of Lycium barbarum (Goji) against major human phase I metabolism enzymes.

BACKGROUND: Goji berry (Lycium barbarum) has been used as traditional Chinese medicine and a functional food in China. Goji tea may interact with drugs such as warfarin by inhibiting the cytochrome P450 (CYP) 2C9, and this study was undertaken to characterize the effect of Goji products on CYP2C9/19-, CYP2D6 *1/*10-, CYP3A4/5/7-, CYP19-, and flavin-containing monooxygenase (FMO) 3-mediated metabolism. METHODS: Goji juice, water, and ethanol extracts were examined for their effect on CYP2C9/19-, 2D6-, 3A4/5/7-, 4A11-, CYP19-, and FMO3-mediated metabolism by using in vitro bioassay. The mechanism-based inactivation (MBI) of Goji juice on CYP3A4 was also examined. RESULTS: Data indicates that both fresh juice and commercially available juice caused strong inhibition (over 75 %) of most of the major CYP450 enzymes and moderate inhibition of FMO3 (30-60 %). Compared to juice, the Goji cold/hot water extracts effected low inhibition (below 30 %) of these enzymes. Ethanol (80 %) extracts exhibit the strongest inhibition on CYP2C9 and 2C19 (over 90 %). The inhibition pattern of dried and fresh berry extract and high-performance liquid chromatography (HPLC)-UV fingerprints were similar. CONCLUSIONS: These findings suggest that Goji products (berries, tea, tincture, and juice) can inhibit phase I drug metabolism enzymes and have the potential to affect the safety and efficacy of therapeutic products.

Phytochemical Comparison of the Water and Ethanol Leaf Extracts of the Cree medicinal plant, Sarracenia purpurea L. (Sarraceniaceae).

PURPOSE: The Cree of Eeyou Istchee in Northern Quebec identified Sarracenia purpurea L. as an important plant for the treatment of Type 2 diabetes. Traditionally the plant is used as a decoction (boiling water extract) of the leaf, however, in order to study the extract in a laboratory setting, an 80% ethanol extract was used. In this study, the phytochemistry of both extracts of the leaves was compared and quantified. METHODS: Two S. purpurea leaf extracts were prepared, one a traditional hot water extract and the other an 80% ethanol extract. Using UPLC-ESI-MS, the extracts were phytochemically compared for 2 triterpenes, betulinic acid and ursolic acid, using one gradient method and for 10 additional substances, including the actives quercetin-3-O-galactoside and morroniside, using a different method. RESULTS: The concentrations of the nine phenolic substances present, as well as an active principle, the iridoid glycoside morroniside, were very similar between the two extracts, with generally slightly higher concentrations of phenolics in the ethanol extract as expected. However, two triterpenes, betulinic acid and ursolic acid, were 107 and 93 times more concentrated, respectively, in the ethanol extract compared to the water extract. CONCLUSION: The main phytochemical markers and most importantly the antidiabetic active principles, quercetin-3-O-galactoside and morroniside, were present in similar amounts in the two extracts, which predicts similar bioactivity.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Evaluation by microarray of the potential safety of Sarracenia purpurea L. (Sarraceniaceae) a traditional medicine used by the Cree of Eeyou Istchee.

PURPOSE: The purpose of this study was to assess safety of the traditional antidiabetic extracts of either S. purpurea or its lead active principle, morroniside at the transcriptional level. The overarching objective was to profile and validate transcriptional changes in the cytochrome P450 family of genes, in response to treatment with S. purpurea ethanolic extract or its lead active, morroniside. METHODS: Transcriptional activity was profiled using a 19K human cDNA microarray in C2BBe1 cells, clone of Caco-2 intestinal cells, which are a model of first-pass metabolism (1, 2). Cells were treated with S. purpurea extract for 4 and 24 hrs, as well as the pure compound morroniside for 4 hrs, to determine their effects. RESULTS: No evidence of cytochrome P450 transcriptome regulation or of transcriptional activation of other diabetes relevant mRNA was detected after rigorous quantitative-PCR validation of microarray results. CONCLUSION: Our data do not support a transcriptional mechanism of action for either S. purpurea extract or its lead active, morroniside. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Melatonin Interaction Resulting in Severe Sedation.

PURPOSE: Natural health products (NHPs), including melatonin, are widely used products. Despite the widespread assumption that all NHPs are safe, they contain pharmacologically active substances and can therefore have adverse effects and/or interact with pharmaceuticals. OBJECTIVE: To investigate the mechanism underlying NHP interactions identified through the Pharmacy SONAR active surveillance study. METHODS: Active surveillance was undertaken in community pharmacies to identify adverse events in patients who had recently taken NHPs together with conventional pharmaceuticals. For suspected NHP-pharmaceutical interactions, the possible mechanism of action was explored by in vitro analysis of samples of different products to identify cytochrome P450 enzyme (CYP) inhibition potential. RESULTS: Active surveillance identified a 19-year-old male taking citalopram, nortriptyline and oxycodone concomitantly and who experienced severe sedation when melatonin was added to this regimen. In vitro analysis involving several melatonin products showed product-dependent inhibition of CYP1A2, CYP2C19 and CYP3A7. CONCLUSION: The adverse event was likely due to a primary pharmacokinetic interaction between melatonin and citalopram; although mechanistically, interactions affecting cytochrome P450-mediated metabolism may have occurred with all of these health products. A pharmacodynamic interaction may also be possible, but beyond the capacity of this study to establish.

Cytochrome P450 3A4 and 2D6-mediated metabolism of leisure and medicinal teas.

PURPOSE: Thirty-five commercially available Camellia sinensis (black and green) and herbal leisure teas and an assortment of Traditional Chinese medicinal teas were randomly selected and examined for their potential to inhibit the drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4). The study was then extended to examine CYP2D6*1 and CYP2D6*10. METHODS: Microtiter fluorometric assays were utilized to examine the potential for the teas to inhibit CYP-mediated metabolism. Aqueous or alcoholic extracts of the dried tea plant material were examined. METHODS: Most of the black and green leisure teas generally inhibited CYP3A4 more than the Chinese medicinal teas. The medicinal Chinese teas were generally more inhibitory towards CYP3A4 compared to the CYP2D6 isozymes, and the aqueous extracts displayed more potency than the alcoholic extracts. CONCLUSIONS: Tea whether used for leisure or medicinal purposes has the potential to inhibit CYP3A4-mediated drug metabolism particularly black tea.

The effect of Cree traditional medicinal teas on the activity of human cytochrome P450-mediated metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhododendron groenlandicum (Bog Labrador tea), Rhododendron tomentosum (Marsh Labrador tea) and Juniperus communis (Juniper) are used in medicinal teas by Canadian aboriginal cultures alone and in combination with conventional drug products. The safety of this combination had not been previously examined and this study was initiated to examine the potential of medicinal teas to inhibit the major human drug metabolizing enzyme, cytochrome P450 3A4 (CYP3A4). MATERIALS AND METHODS: The decoctions of Rhododendron groenlandicum and Rhododendron tomentosum leaves and Juniperus communis berries were examined in a microtiter fluorometric assay to examine their potential to inhibit CYP-mediated metabolism. RESULTS: The decoctions showed progressive inhibition towards CYP3A4 the longer the leaves or berries were brewed. R. Rhododendron groenlandicum and Juniperus communis may have the potential to inhibit CYP3A4-mediated metabolism. CONCLUSIONS: The findings of this study with these traditional medicines are significant in that they provide mechanistic support that these products have the potential to affect the safety and efficacy of other health and medicinal products. As this study only examined CYP3A4, it is possible that these medicinals contain substances that could also affect other metabolic enzymes.

Antimicrobial and P450 inhibitory properties of common functional foods.

PURPOSE: To study the effect of functional foods on human cytochrome P450 (CYP) and the gut bacterial microflora that may potentially affect drug metabolism and ultimately affect human health and wellness. METHODS: This study examined a variety of food plants from the Apiaceae, Fabaceae, and Lamiaceae families for their inhibitory potential on cytochrome 2D6-, 3A4-, 3A5-, and 3A7-mediated metabolism. The antimicrobial effects of these samples were also investigated with 7 selected bacterial surrogate species to determine potential effects on the gut microflora. RESULTS: The highest CYP inhibitory activities, based upon visual examination, were observed from extracts of celery seed, cumin, fennel seed, basil, oregano, and rosemary belonging to the Apiaceae and Lamiaceae families, respectively. Likewise, the strongest antimicrobial activities were also observed in the Apiaceae and Lamiaceae. No significant antimicrobial and CYP inhibition was observed in the Fabaceae extracts. CONCLUSION: Results demonstrated the possible risk of food-drug interactions from spice and herb plants may affect drug disposition and safety.

Pharmacy study of natural health product adverse reactions (SONAR): a cross-sectional study using active surveillance in community pharmacies to detect adverse events associated with natural health products and assess causality.

OBJECTIVES: To investigate the rates and causality of adverse event(s) (AE) associated with natural health product (NHP) use, prescription drug use and concurrent NHP-drug use through active surveillance in community pharmacies. DESIGN: Cross-sectional study of screened patients. SETTING: 10 community pharmacies across Alberta and British Columbia, Canada from 14 January to 30 July 2011. PARTICIPANTS: The participating pharmacy staff screened consecutive patients, or agents of patients, who were dropping or picking up prescription medications. PRIMARY OUTCOME MEASURES: Patients were screened to determine the proportions of them using prescription drugs and/or NHPs, as well as their respective AE rates. All AEs reported by the screened patients who took a NHP, consented to, and were available for, a detailed telephone interview (14%) were adjudicated fully to assess for causality. RESULTS: Over a total of 105 pharmacy weeks and 1118 patients screened, 410 patients reported taking prescription drugs only (36.7%; 95% CI 33.9% to 39.5%), 37 reported taking NHPs only (3.3%; 95% CI 2.4% to 4.5%) and 657 reported taking prescription drugs and NHPs concurrently (58.8%; 95% CI 55.9% to 61.6%). In total, 54 patients reported an AE, representing 1.2% (95% CI 0.51% to 2.9%), 2.7% (95% CI 0.4% to 16.9%) and 7.3% (95% CI 5.6% to 9.6%) of each population, respectively. Compared with patients who reported using prescription drugs, the patients who reported using prescription drugs and NHPs concurrently were 6.4 times more likely to experience an AE (OR; 95% CI 2.52 to 16.17; p<0.001). Combined with data from Ontario, Canada, a national proportion was calculated, which found that 45.4% (95% CI 43.8% to 47.0%) of Canadians who visit community pharmacies take NHPs and prescription drugs concurrently, and of those, 7.4% (95% CI 6.3% to 8.8%) report an AE. CONCLUSIONS: A substantial proportion of community pharmacy patients use prescription drugs and NHPs concurrently; these patients are at a greater risk of experiencing an AE. Active surveillance provides a means of detecting such AEs and collecting high-quality data on which causality assessment can be based.

In vitro inhibition of metabolism but not transport of gliclazide and repaglinide by Cree medicinal plant extracts.

ETHNOPHARMACOLOGICAL RELEVANCE: Interactions between conventional drug and traditional medicine therapies may potentially affect drug efficacy and increase the potential for adverse reactions. Cree traditional healing is holistic and patients may use medicinal plants simultaneously with the conventional drugs. However, there is limited information that these medicinal plants may interact with drugs and additional mechanistic information is required. In this study, extracts from traditionally used Cree botanicals were assessed for their potential interaction that could alter the disposition of two blood glucose lowering drugs, gliclazide (Diamicron) and repaglinide (Gluconorm) though inhibition of either metabolism or transport across cell membranes. MATERIALS AND METHODS: The effect of 17 extracts on metabolism was examined in a human liver microsome assay by HPLC and individual cytochrome P450s 2C9, 2C19, 2C8 and 3A4 in a microplate fluorometric assay. Gliclazide, rhaponticin and its aglycone derivative, rhapontigenin were also examined in the fluorometric assay. The effect on transport was examined with 11 extracts using the intestinal epithelial Caco-2 differentiated cell monolayer model at times up to 180 min. RESULTS: Both blood glucose lowering medications, gliclazide and repaglinide traversed the Caco-2 monolayer in a time-dependent manner that was not affected by the Cree plant extracts. Incubation of the Cree plant extracts inhibited CYP2C9, 2C19, 2C8 and 3A4-mediated metabolism, and the formation of four repaglinide metabolites: M4, m/z 451-A, m/z 451-B and the glucuronide of repaglinide in the human liver microsome assay. Gliclazide caused no significant inhibition. Likewise, rhaponticin had little effect on the enzymes causing changes of less than 10% with an exception of 17% inhibition of CYP2C19. By contrast, the aglycone rhapontigenin showed the greatest effects on all CYP-mediated metabolism. Its inhibition ranged from a mean of 58% CYP3A4 inhibition to 89% inhibition of CYP2C9. While rhaponticin and the aglycone did not show significant effects on repaglinide metabolism, they demonstrated inhibition of gliclazide metabolism. The aglycone significantly affected levels of gliclazide and its metabolites. CONCLUSION: These studies demonstrate that the Cree plant extracts examined have the potential in vitro to cause drug interactions through effects on key metabolic enzymes.

Study of natural health product adverse reactions (SONAR): active surveillance of adverse events following concurrent natural health product and prescription drug use in community pharmacies.

BACKGROUND: Many consumers use natural health products (NHPs) concurrently with prescription medications. As NHP-related harms are under-reported through passive surveillance, the safety of concurrent NHP-drug use remains unknown. To conduct active surveillance in participating community pharmacies to identify adverse events related to concurrent NHP-prescription drug use. METHODOLOGY/PRINCIPAL FINDINGS: Participating pharmacists asked individuals collecting prescription medications about (i) concurrent NHP/drug use in the previous three months and (ii) experiences of adverse events. If an adverse event was identified and if the patient provided written consent, a research pharmacist conducted a guided telephone interview to gather additional information after obtaining additional verbal consent and documenting so within the interview form. Over a total of 112 pharmacy weeks, 2615 patients were screened, of which 1037 (39.7%; 95% CI: 37.8% to 41.5%) reported concurrent NHP and prescription medication use. A total of 77 patients reported a possible AE (2.94%; 95% CI: 2.4% to 3.7%), which represents 7.4% of those using NHPs and prescription medications concurrently (95%CI: 6.0% to 9.2%). Of 15 patients available for an interview, 4 (26.7%: 95% CI: 4.3% to 49.0%) reported an AE that was determined to be "probably" due to NHP use. CONCLUSIONS/SIGNIFICANCE: Active surveillance markedly improves identification and reporting of adverse events associated with concurrent NHP-drug use. Although not without challenges, active surveillance is feasible and can generate adverse event data of sufficient quality to allow for meaningful adjudication to assess potential harms.

The effect of ß-carotene supplementation on the pharmacokinetics of nelfinavir and its active metabolite M8 in HIV-1-infected patients.

ß-Carotene supplements are often taken by individuals living with HIV-1. Contradictory results from in vitro studies suggest that ß-carotene may inhibit or induce cytochrome P450 enzymes and transporters. The study objective was to investigate the effect of ß-carotene on the steady-state pharmacokinetics of nelfinavir and its active metabolite M8 in HIV-1 infected individuals. Twelve hour nelfinavir pharmacokinetic analysis was conducted at baseline and after 28 days of ß-carotene supplementation (25,000 IU twice daily). Nelfinavir and M8 concentrations were measured with validated assays. Non-compartmental methods were used to calculate the pharmacokinetic parameters. Geometric mean ratios comparing day 28 to day 1 area under the plasma concentration-time curve (AUC(0-12 h)), maximum (C(max)) and minimum (C(min)) concentrations of nelfinavir and M8 are presented with 90% confidence intervals. Eleven subjects completed the study and were included in the analysis. There were no significant differences in nelfinavir AUC(0-12 h) and C(min) (-10%, +4%) after ß-carotene supplementation. The M8 C(min) was increased by 31% while the M8 AUC(0-12 h) and C(max) were unchanged. During the 28 day period, mean CD4+ % and CD4+:CD8+ ratio increased significantly (p < 0.01). ß-carotene supplementation increased serum carotene levels but did not cause any clinically significant difference in the nelfinavir and M8 exposure.

Inhibition of human cytochrome p450 metabolism by blended herbal products and vitamins.

PURPOSE: The use of supplements as herbal and micronutrient natural health products with conventional health products has become increasingly popular. It has been reported that some herbal products can inhibit the activity of cytochrome P450-mediated metabolism and drug disposition. This study was designed to investigate a case report of a severe adverse event to determine the potential interactions of femMED, Thyrosense and vitamins on cytochrome P450-mediated drug metabolism. METHODS: The effect of extracts from these commercially available herbal formulations, trans-ß-carotene, multivitamins, and vitamin D3 supplements on cytochrome P450-mediated drug metabolism of marker substrates was determined in vitro. RESULTS: The blended herbal products femMED and Thyrosense had a high potential to affect the safety and efficacy of many health products. Some vitamin and trans-ß-carotene containing products also have the potential to affect drug disposition. The tBC content of various products was analyzed and significant discrepancies were found among them and between values indicated on product labels. Product extracts also exhibited a low to moderate capacity to inhibit cytochrome P450 2C9, 2C19 and 3A4-mediated metabolism. CONCLUSIONS: The findings of this study suggest that these herbal products and most vitamin products may have an inhibitory effect on cytochrome P450 activity that could contribute to development of an adverse event. Further work is warranted to determine how supplementation with these products may affect drug metabolism in an in vivo context.

Comparative study of hops-containing products on human cytochrome P450-mediated metabolism.

The potential for 15 different ales (6), ciders (2 apple and 1 pear), and porters (6) and 2 non-alcoholic products to affect cytochrome P450 (CYP)-mediated biotransformation and P-glycoprotein-mediated efflux of rhodamine was examined. As in our previous study, a wide range of recovered nonvolatile suspended solids dry weights were noted. Aliquots were also found to have varying effects on biotransformation and efflux. Distinct differences in product ability to affect the safety and efficacy of therapeutic products confirmed our initial findings that some porters (stouts) have a potential to affect the safety and efficacy of health products metabolized by CYP2D6 and CYP3A4 isozymes. Most products, except 2 of the ciders and the 2 non-alcoholic products, also have the potential to affect the safety of CYP2C9 metabolized medications and supplements. Further studies are required to determine the clinical significance of these findings.

Extracts of Canadian first nations medicinal plants, used as natural products, inhibit neisseria gonorrhoeae isolates with different antibiotic resistance profiles.

BACKGROUND: Neisseria gonorrhoeae (Ng) has developed resistance to most antimicrobial agents and the antibiotics recommended for therapy are restricted, for the most part, to third generation cephalosporins. In order to investigate new potential sources of antimicrobial agents, the antibacterial properties of 14 Canadian plants used in traditional First Nations' medicine were tested against Ng isolates having differing antimicrobial susceptibility profiles. METHODS: Ethanolic extracts of 14 Canadian botanicals, analyzed by high-performance liquid chromatography, were tested for their antimicrobial activity (disc diffusion and/or agar dilution assays) against susceptible Ng reference strains and a panel of 28 Ng isolates with various antimicrobial resistance profiles. RESULTS: Extracts of Arctostaphylos uva ursi (kinnikinnick or bearberry), Hydrastis canadensis (goldenseal), Prunus serotina (black cherry), and Rhodiola rosea (roseroot) inhibited the growth of all Ng isolates with minimum inhibitory concentrations of 32 µg/mL, 4 to 32 µg/mL, 16 to >32 µg/mL, and 32 to 64 µg/mL, respectively. Extracts of Acorus americanus (sweet flag), Berberis vulgaris (barberry), Cimicifuga racemosa (black cohosh), Equisetum arvense (field horsetail), Gaultheria procumbens (wintergreen), Ledum groenlandicum (Labrador tea), Ledum palustre (marsh Labrador tea), Oenothera biennis (common evening primrose), Sambucus nigra (elderberry), and Zanthoxylum americanum (prickly ash) had weak or no antimicrobial activity against the Ng isolates with minimum inhibitory concentrations ≥256 µg/mL. The phytochemical berberine from H. canadensis inhibited the growth of all Ng isolates. The phytochemicals, salidroside and rosavin, present in R. rosea, also showed inhibitory activity against Ng strains. CONCLUSION: Canadian botanicals represent a potential source of novel compounds which inhibit Ng, including isolates resistant to antibiotics.

Cree antidiabetic plant extracts display mechanism-based inactivation of CYP3A4.

Seventeen Cree antidiabetic medicinal plants were studied to determine their potential to inhibit cytochrome P450 3A4 (CYP3A4) through mechanism-based inactivation (MBI). The ethanolic extracts of the medicinal plants were studied for their inhibition of CYP3A4 using the substrates testosterone and dibenzylfluorescein (DBF) in high pressure liquid chromatography (HPLC) and microtiter fluorometric assays, respectively. Using testosterone as a substrate, extracts of Alnus incana, Sarracenia purpurea, and Lycopodium clavatum were identified as potent CYP3A4 MBIs, while those from Abies balsamea, Picea mariana, Pinus banksiana, Rhododendron tomentosum, Kalmia angustifolia, and Picea glauca were identified as less potent inactivators. Not unexpectedly, the other substrate, DBF, showed a different profile of inhibition. Only A. balsamea was identified as a CYP3A4 MBI using DBF. Abies balsamea displayed both NADPH- and time-dependence of CYP3A4 inhibition using both substrates. Overall, several of the medicinal plants may markedly deplete CYP3A4 through MBI and, consequently, decrease the metabolism of CYP3A4 substrates including numerous medications used by diabetics.

The effect of natural health products and traditional medicines on the activity of human hepatic microsomal-mediated metabolism of oseltamivir.

PURPOSE: Oseltamivir is a prodrug that requires metabolic activation but there is little information on whether natural health products interact to prevent the biotransformation by the carboxylesterase. METHODS: HPLC-DAD-ESI-MSD and fluorometric assays were used to determine if 50-pooled mixed gender human liver microsomes can mediate the formation of the active carboxylate metabolite and then if this reaction is affected by natural health products. RESULTS: Extracts from 6 traditional Cree botanicals, a commercially available Echinacea product, Goldenseal and a traditional Chinese medicine reduced the formation of the active drug. In addition to oseltamivir carboxylate we report the detection of two new metabolites which are derivatives of oseltamivir carboxylate, one of which is a metabonate formed as a result of methanol. CONCLUSIONS: In vitro studies would suggest that there is the potential for some natural health products used by patients in response to pandemic A/H1N1 to reduce drug efficacy. Further studies are required to determine if these potential interactions could be clinically significant.

In vitro inhibitory effect of West African medicinal and food plants on human cytochrome P450 3A subfamily.

AIM OF THE STUDY: In Africa, medicinal plants are used intensively and concomitantly with allopathic medicines in the treatment of opportunity diseases by many patients or by healthy person to prevent diseases. However, there is little information about the interactions between medicines and botanical products used currently in West Africa area. Therefore, the aim of the present investigation is to study the effect of some plant products on CYP3A4, CYP3A5 and CYP3A7, three individual enzymes of CYP3A subfamily, in vitro. MATERIALS AND METHODS: Teas and ethanolic extracts of medicinal, food and co-administered plants were evaluated on CYP3A4, CYP3A5 and CYP3A7 individual enzymes in vitro using fluorometric assays. RESULTS: Extracts of adjuvant plants such as Aframomum cuspidatum, and Aframomum melegueta, as well as one medicinal plant (Harrisonia abyssinica) inhibited CYP3A4, CYP3A5 and CYP3A7 activity more than 90%. Phyllanthus amarus showed high inhibition of CYP3A5 and CYP3A7. Food plants (Solanum macrocarpon and Talinum triangulare) inhibited CYP3A4 and CYP3A5 less than 20%. CONCLUSION: These results indicate that plants tested in this study affect in vitro the activity of the main three CYP3A subfamily enzymes. These active plants could interfere with the metabolism at phase I of conventional drugs in vivo as well act as pharmacoenhancers in herbal mixtures.