RESUMO
There has been a growing interest in hydroxytyrosol (HT) due to its powerful antioxidant and free-radical scavenging properties when added to formulations such as pharmaceuticals and cosmetics. To study the stability and transdermal properties of hydrogels and creams (HT-based formulations), a high-performance liquid chromatography method was developed for determining HT. In the Franz diffusion cell system, both hydrogel and cream show a rapid and similar penetration profile through the Bama miniature pig skin. However, the Strat-M® membrane exhibits slightly lower permeability and is selective to different formulations; that is, the cream has a permeability value of 10.69%, while the hydrogel has a value of 5.27%. The dynamics parameters from the permeation assays indicate that the model using the Strat-M® membrane can be used as a screening tool to evaluate the skin uptake and permeation efficacy of different formulations. Adding 3-O-ethyl-L-ascorbic acid to HT-based formulations can effectively prevent discoloration under prolonged high-temperature storage, while combining multiple antioxidants delays degradation most effectively. This study provides novel ideas for functional formulation optimization to enhance the realism and reproducibility of cosmetic products containing HT and provides scientific evidence for the production, packaging, shelf life, storage, and transportation of products.
Assuntos
Antioxidantes , Estabilidade de Medicamentos , Permeabilidade , Álcool Feniletílico , Absorção Cutânea , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/química , Álcool Feniletílico/farmacocinética , Álcool Feniletílico/administração & dosagem , Animais , Suínos , Absorção Cutânea/efeitos dos fármacos , Antioxidantes/química , Antioxidantes/administração & dosagem , Antioxidantes/farmacocinética , Pele/metabolismo , Hidrogéis/química , Administração Cutânea , Porco Miniatura , Creme para a Pele/química , Química Farmacêutica/métodos , Cromatografia Líquida de Alta Pressão , Ácido Ascórbico/químicaRESUMO
Nowadays, increasing interest in olive pomace (OP) valorization aims to improve olive's industry sustainability. Interestingly, several studies propose a high-value application for OP extracts containing its main phenolic compounds, hydroxytyrosol and oleuropein, as therapy for ocular surface diseases. In this work, the stability and accessibility of OP total phenolic and flavonoid content, main representative compounds, and antioxidant activity were assessed under different pretreatment conditions. Among them, lyophilization and supercritical CO2 extraction were found to increase significantly most responses measured in the produced extracts. Two selected extracts (CONV and OPT3) were obtained by different techniques (conventional and pressurized liquid extraction); Their aqueous solutions were characterized by HPLC-DAD-MS/MS. Additionally, their safety and stability were evaluated according to EMA requirements towards their approval as ophthalmic products: their genotoxic effect on ocular surface cells and their 6-months storage stability at 4 different temperature/moisture conditions (CPMP/ICH/2736/99), together with pure hydroxytyrosol and oleuropein solutions. The concentration of hydroxytyrosol and oleuropein in pure or extract solutions was tracked, and possible degradation products were putatively identified by HPLC-DAD-MS/MS. Hydroxytyrosol and oleuropein had different stability as standard or extract solutions, with oleuropein also showing different degradation profile. All compounds/extracts were safe for ophthalmic use at the concentrations tested.
Assuntos
Olea/química , Fenóis/química , Extratos Vegetais/farmacocinética , Aldeídos/química , Aldeídos/farmacocinética , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Ensaio Cometa , Córnea/citologia , Córnea/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Humanos , Soluções Oftálmicas/química , Soluções Oftálmicas/farmacologia , Fenóis/farmacocinética , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/química , Álcool Feniletílico/farmacocinética , Extratos Vegetais/química , Espectrometria de Massas em TandemRESUMO
Lipophenols are regarded as an emerging source of functional food ingredients. However, little is known about their in vivo digestion, absorption, and metabolism. Thus, the pharmacokinetic characteristics in rat and the gut microbial degradation of tyrosol acyl esters (TYr-Es) with fatty acids of C12:0, C18:0, and C18:2 were investigated for the first time. Major metabolites including tyrosol sulfate and tyrosol glucuronide, rather than the parent compounds, were detected in rat plasma after oral administration of TYr-Es. The increased plasma half-life (T1/2) and mean residence time demonstrated that TYr-Es display a longer duration of action in vivo than TYr, potentially leading to higher oral bioavailability. TYr-Es could be hydrolyzed by the gut microbiota to free TYr, which may result in the appearance of the second absorption peak in pharmacokinetic profiles. Therefore, TYr-Es exhibit improved bioavailability compared to that of TYr because of their prolonged duration of action.
Assuntos
Ésteres/farmacocinética , Álcool Feniletílico/análogos & derivados , Animais , Disponibilidade Biológica , Ésteres/química , Ácidos Graxos/sangue , Ácidos Graxos/química , Cinética , Masculino , Álcool Feniletílico/química , Álcool Feniletílico/farmacocinética , Plasma/química , Ratos , Ratos Sprague-DawleyRESUMO
Hypoxia inducible factor and nuclear factor-kappa beta pathways have been proposed as therapeutic targets for several inflammatory diseases. Caffeic acid phenethyl ester (CAPE) and piceatannol (PIC) are natural anti-inflammatory compounds; however, poor bioavailability and limited understanding of biomolecular mechanistic limits its clinical use. The aims of this study are to enhance bioavailability and investigate their impact on nuclear p65 and HIF-1α for the first time in experimental colitis.Dextran sulphate sodium was used to induce colitis in mice and effect of either free CAPE/PIC or CAPE/PIC loaded albumin nanoparticles treatment was observed on disease development and levels of cellular p65 and HIF-1α.Our results indicate that albumin nano-encapsulation of CAPE/PIC not only enhances its anti-inflammatory potential but also potentiates its ability to effectively modulate inflammation related biomolecular pathways. Hence, combining nanotechnology with natural compounds could result in development of new therapeutic options for IBD.
Assuntos
Albuminas/química , Ácidos Cafeicos/administração & dosagem , Colite/tratamento farmacológico , Sulfato de Dextrana/efeitos adversos , Álcool Feniletílico/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Estilbenos/administração & dosagem , Animais , Disponibilidade Biológica , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacocinética , Colite/induzido quimicamente , Colite/metabolismo , Modelos Animais de Doenças , Combinação de Medicamentos , Composição de Medicamentos , Sinergismo Farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Tamanho da Partícula , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/química , Álcool Feniletílico/farmacocinética , Estilbenos/química , Estilbenos/farmacocinética , Fator de Transcrição RelA/metabolismoRESUMO
Alperujo-a two-phase olive mill waste that is composed of olive vegetation water and solid skin, pulp, and seed fragments - is a highly valuable olive by-product due to its high content in phenolic compounds. In this study, we assessed whether ß-cyclodextrin (ß-CD), which is used to extract and protect alpejuro phenolic compounds (hydroxytyrosol-O-glucoside, tyrosol, caffeic, and p-coumaric acids) could impact on their bioaccessibility (i.e., the percentage of molecule found in the aqueous phase of the digesta) and uptake by intestinal cells, by using an in vitro digestion model and Caco-2 TC7 cells in culture, respectively. Our results showed that ß-CD did not change the bioaccessibility of the selected phenols. Hydroxytyrosol-O-glucoside and caffeic did not cross Caco-2 cell monolayers. Conversely ferulic acid, identified as the main caffeic acid intestinal metabolite, was absorbed through intestinal cell monolayers (~20%). Interestingly, ß-CD moderately but significantly improved the local absorption of tyrosol and p-coumaric acid (2.3 + 1.4% and 8.5 ± 4.2%, respectively, p < 0.05), even if their final bioavailability (expressed as bioaccessibility × absorption by Caco-2 cells) was not modified (16.2 ± 0.6% vs. 16.8 ± 0.5% for tyrosol and 32.0 ± 3.2% vs. 37.2 ± 3.2% for p-coumaric acid, from pure alperujo and alperujo complexed with ß-CD, respectively). Overall, our results show that ß-CD is an interesting extraction and storage agent for phenolic compounds that does not alter their in vitro bioavailability.
Assuntos
Olea/química , Fenóis/farmacocinética , beta-Ciclodextrinas/farmacologia , Antioxidantes/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Ácidos Cafeicos/farmacocinética , Ácidos Cumáricos , Glucosídeos/farmacocinética , Humanos , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/farmacocinética , Extratos Vegetais/farmacologia , Propionatos/farmacocinéticaRESUMO
To prevent implant failure due to fibrosis is a major objective in glaucoma research. The present study investigated the antifibrotic effects of paclitaxel (PTX), caffeic acid phenethyl ester (CAPE), and pirfenidone (PFD) coated microstent test specimens in a rat model. Test specimens based on a biodegradable blend of poly(4-hydroxybutyrate) biopolymer and atactic poly(3-hydroxybutyrate) (at.P(3HB)) were manufactured, equipped with local drug delivery (LDD) coatings, and implanted in the subcutaneous white fat depot. Postoperatively, test specimens were explanted and analyzed for residual drug content. Fat depots including the test specimens were histologically analyzed. In vitro drug release studies revealed an initial burst for LDD devices. In vivo, slow drug release of PTX was found, whereas it already completed 1 week postoperatively for CAPE and PFD LDD devices. Histological examinations revealed a massive cell infiltration in the periphery of the test specimens. Compact fibrotic capsules around the LDD devices were detectable at 4-36 weeks and least pronounced around PFD-coated specimens. Capsules stained positive for extracellular matrix (ECM) components. The presented model offers possibilities to investigate release kinetics and the antifibrotic potential of drugs in vivo as well as the identification of more effective agents for a novel generation of drug-eluting glaucoma microstents.
Assuntos
Ácidos Cafeicos/administração & dosagem , Sistemas de Liberação de Medicamentos/instrumentação , Stents Farmacológicos , Paclitaxel/administração & dosagem , Álcool Feniletílico/análogos & derivados , Piridonas/administração & dosagem , Animais , Ácidos Cafeicos/farmacocinética , Ácidos Cafeicos/uso terapêutico , Fibrose , Glaucoma/terapia , Masculino , Paclitaxel/farmacocinética , Paclitaxel/uso terapêutico , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/farmacocinética , Álcool Feniletílico/uso terapêutico , Piridonas/farmacocinética , Piridonas/uso terapêutico , Ratos , Ratos WistarRESUMO
Caffeic acid phenethyl ester (CAPE) is a bioactive polyphenolic compound obtained from propolis extract. Although it has a broad therapeutic potential, the bioavailability of CAPE is limited, due to reduced solubility and poor plasmatic stability. Efforts to reduce these pharmacokinetic drawbacks resulted in the synthesis of caffeic acid phenethyl amide (CAPA). Cyclodextrins have been proved as promising excipients for the formulation of active ingredients. Herein, we report the inclusion complexation behavior and binding ability of CAPE and CAPA with hydroxypropyl-ß-cyclodextrin (HP-ß-CD). The supramolecular interactions were examined through UV and FTIR spectroscopy, DSC, 1H NMR and 2D ROESY. The CAPE/HP-ß-CD and CAPA/HP-ß-CD inclusion complexes stability constants were determined to be, respectively, 2911.6 and 584.6â¯M-1 in water and 2866.2 and 700.1â¯M-1 at physiological pH. The aqueous solubility increased notably, proving that HP-ß-CD can be potentially useful to improve the biological, chemical and physical properties of CAPE and CAPA.
Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Ácidos Cafeicos/química , Composição de Medicamentos/métodos , Álcool Feniletílico/análogos & derivados , Ácidos Cafeicos/farmacocinética , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Álcool Feniletílico/química , Álcool Feniletílico/farmacocinética , Solubilidade , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
PURPOSE: To date, several in vitro and in vivo studies have shown phenolic compounds occurring naturally in olives and olive oil to be beneficial to human health due to their interaction with intracellular signaling pathways. However, the bioavailability of the most important of these compounds, hydroxytyrosol (HT), and its transformation into derivatives within the organism after oral intake are still not completely understood, requiring further in vivo research. This study deals with the differential bioavailability and metabolism of oral HT and its derivatives in rats. METHODS: Hydroxytyrosol (HT), hydroxytyrosol acetate (HTA), and 2,3-dihydroxyphenylacetic acid (DOPAC) were administered at doses of 1 and 5 mg/kg to Sprague-Dawley rats (n = 9 per treatment) by oral gavage. Their plasma kinetics and absorption ratio, assessed as their excretion in 24-h urine, were determined by UHPLC/MS/MS. RESULTS: Plasma and urine levels indicated that although the three compounds are efficiently absorbed in the gastrointestinal tract and show similar metabolism, the bioavailability is strongly dependent on the derivative considered, dosage, and gender. Inter-conversion among them has been described also, suggesting an interaction with internal routes. Microbiota metabolites derived from these phenolics were also taken into account; thereby, homovanillic alcohol and tyrosol were identified and quantified in urine samples after enzymatic de-conjugation, concluding the metabolic profile of HT. CONCLUSIONS: Our results suggest that different dosages of HT, HTA, and DOPAC do not provide a linear, dose-dependent plasma concentration or excretion in urine, both of which can be affected by the saturation of first-phase metabolic processes and intestinal transporters.
Assuntos
Ácido 3,4-Di-Hidroxifenilacético/farmacocinética , Fenóis/farmacocinética , Álcool Feniletílico/análogos & derivados , Fatores Sexuais , Ácido 3,4-Di-Hidroxifenilacético/administração & dosagem , Ácido 3,4-Di-Hidroxifenilacético/sangue , Ácido 3,4-Di-Hidroxifenilacético/urina , Administração Oral , Animais , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Feminino , Ácido Homovanílico/urina , Masculino , Azeite de Oliva/administração & dosagem , Fenóis/administração & dosagem , Fenóis/sangue , Fenóis/urina , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/sangue , Álcool Feniletílico/farmacocinética , Álcool Feniletílico/urina , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em TandemRESUMO
BACKGROUND: The Mediterranean diet includes olive oil as its primary source of fat. This diet is frequently associated to longevity and a lower incidence of chronic diseases due to its biological activities and health effects. Apart from oleic acid, olive oil contains many bioactive components including polyphenols that have been reported to exert antioxidant and anti-inflammatory activities. Polyphenols may almost in part be responsible for the protective effects against cardiovascular diseases associated with olive oil. OBJECTIVE: To review and discuss the available literature on hydroxytyrosol effects as a cardioprotective agent. Moreover, we also discuss the chemistry, nutritional aspects and bioavailability of hydroxytyrosol. RESULTS: Hydroxytyrosol is one of the major phenolic compounds in olive oil and has demonstrated strong radical-scavenging properties. Several studies have been performed in order to look further into the effects of the polyphenol hydroxytyrosol in relation to cardiovascular events and illnesses in animal trials and in vitro. However, no clinical trials have focused on the specific action of hydroxytyrosol and cardiovascular diseases, although some are being undertaken to look at olive oil or olive leaf extract properties. CONCLUSION: Hydroxytyrosol from olive oil exerts antioxidant, anti-inflammatory, anti-platelet aggregation and ati-atherogenic activities in in vitro and animal models. However, its possible therapeutic use in humans requires additional clinical trials.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Azeite de Oliva/química , Álcool Feniletílico/análogos & derivados , Inibidores da Agregação Plaquetária/uso terapêutico , Animais , Disponibilidade Biológica , Humanos , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Álcool Feniletílico/química , Álcool Feniletílico/farmacocinética , Álcool Feniletílico/uso terapêutico , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologiaRESUMO
Phenylethanoid glycosides (PhGs) are widely distributed in traditional Chinese medicines as well as in other medicinal plants, and they were characterized by a phenethyl alcohol (C6-C2) moiety attached to a ß-glucopyranose/ß-allopyranose via a glycosidic bond. The outstanding activity of PhGs in diverse diseases proves their importance in medicinal chemistry research. This review summarizes new findings on PhGs over the past 10 years, concerning the new structures, their bioactivities, including neuroprotective, anti-inflammatory, antioxidant, antibacterial and antivirus, cytotoxic, immunomodulatory, and enzyme inhibitory effects, and pharmacokinetic properties.
Assuntos
Medicamentos de Ervas Chinesas , Glicosídeos , Álcool Feniletílico , Plantas Medicinais/química , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Antioxidantes/química , Antioxidantes/isolamento & purificação , Antioxidantes/farmacocinética , Antioxidantes/uso terapêutico , Antivirais/química , Antivirais/isolamento & purificação , Antivirais/farmacocinética , Antivirais/uso terapêutico , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/uso terapêutico , Glicosídeos/química , Glicosídeos/isolamento & purificação , Glicosídeos/farmacocinética , Glicosídeos/uso terapêutico , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Fatores Imunológicos/farmacocinética , Fatores Imunológicos/uso terapêutico , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/uso terapêutico , Álcool Feniletílico/química , Álcool Feniletílico/isolamento & purificação , Álcool Feniletílico/farmacocinética , Álcool Feniletílico/uso terapêuticoRESUMO
Hydroxytyrosol and tyrosol are dietary phenolic compounds present in virgin olive oil and wine. Both compounds are also endogenously synthesized in our body as byproducts of dopamine and tyramine metabolisms, respectively. Over the last decades, research into hydroxytyrosol and tyrosol has experienced an increasing interest due to the role that these compounds may play in the prevention of certain pathologies (e.g. cardiovascular, metabolic, neurodegenerative diseases and cancer). The translation of promising in vitro and in vivo biological effects from preclinical studies to the context of human disease prevention initially depends on whether the dose ingested becomes available at the site of action. In this regard, information regarding the bioavailability and metabolic disposition of hydroxytyrosol and tyrosol is of most importance to evaluate the impact they may have on human health. In this review, we discuss and summarize the state of the art of the scientific evidence regarding the processes of absorption, distribution, metabolism and excretion of both hydroxytyrosol and tyrosol. We also examine the impact of these compounds and their metabolites on biological activity in terms of beneficial health effects. Finally, we evaluate the different analytical approaches that have been developed to measure the plasma and urinary levels of hydroxytyrosol, tyrosol and their metabolites.
Assuntos
Álcool Feniletílico/análogos & derivados , Disponibilidade Biológica , Dopamina/metabolismo , Humanos , Álcool Feniletílico/sangue , Álcool Feniletílico/metabolismo , Álcool Feniletílico/farmacocinética , Álcool Feniletílico/urina , Distribuição Tecidual , Tiramina/metabolismoRESUMO
The objective of this study was to investigate the in-vivo behavior of topically applied cationic polymeric chitosan nanoparticles (CSNPs) loaded with anti-inflammatory (hydrocortisone, HC) and antimicrobial (hydroxytyrosol, HT) drugs, to elucidate their skin targeting potential for the treatment of atopic dermatitis (AD). Compared to the commercial formulation, the HC-HT loaded CSNPs showed significantly improved drug penetration into the epidermal and dermal layers of albino Wistar rat skin without saturation. Dermal pharmacokinetic of CSNPs with a size of 228.5±7nm and +39±5mV charges revealed that they penetrated 2.46-fold deeper than the commercial formulation did, and had greater affinity at the skin target site without spreading to the surrounding tissues, thereby providing substantial safety benefits. In repeated dermal application toxicity studies, the HC-HT CSNPs showed no evidence of toxicity compared to the commercial formulation, which induced skin atrophy and higher liver enzyme levels. In conclusion, the positively charged HC-HT CSNP formulation exhibited promising local delivery and virtually no treatment-related toxicities, suggesting it may be an efficient and viable alternative for commercially available AD treatments.
Assuntos
Dermatite Atópica/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Hidrocortisona/administração & dosagem , Hidrocortisona/uso terapêutico , Nanopartículas/administração & dosagem , Nanopartículas/metabolismo , Pele/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Quitosana/administração & dosagem , Quitosana/química , Dermatite Atópica/metabolismo , Sistemas de Liberação de Medicamentos/efeitos adversos , Hidrocortisona/química , Hidrocortisona/farmacocinética , Nanopartículas/efeitos adversos , Nanopartículas/química , Tamanho da Partícula , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/química , Álcool Feniletílico/farmacocinética , Álcool Feniletílico/farmacologia , Ratos , Pele/efeitos dos fármacos , Absorção CutâneaRESUMO
Considering that nitrocatechols present putative effects against Parkinson's disease, the absorption and metabolism of nitroderivatives of hydroxytyrosol (HT) were assessed using human cell model systems. The test compounds nitrohydroxytyrosol (NO2HT), nitrohydroxytyrosyl acetate (NO2HT-A), and ethyl nitrohydroxytyrosyl ether (NO2HT-E) were efficiently transferred across human Caco-2 cell monolayers as an intestinal barrier model, NO2HT-A and NO2HT-E being better (p < 0.05) absorbed (absorption rate (AR) = 1.4 ± 0.1 and 1.5 ± 0.2, respectively) than their precursor, NO2HT (AR = 1.1 ± 0.1). A significant amount of the absorbed compounds remained unconjugated (81, 70, and 33% for NO2HT, NO2HT-A, and NO2HT-E, respectively) after incubation in Caco-2 cells, being available for hepatic metabolism. Nitrocatechols were extensively taken up and metabolized by human hepatoma HepG2 cells as a model of the human liver. Both studies revealed extensive hydrolysis of NO2HT-A into NO2HT, whereas NO2HT-E was not hydrolyzed. Glucuronide (75-55%), methylglucuronide (25-33%), and methyl derivatives (0-12%) were the main nitrocatechol metabolites detected after metabolism in Caco-2 and HepG2 cells. In conclusion, NO2HT, NO2HT-A, and NO2HT-E show high in vitro bioavailability and are extensively metabolized by hepatic cells.
Assuntos
Mucosa Intestinal/metabolismo , Fígado/metabolismo , Nitrocompostos/metabolismo , Nitrocompostos/farmacocinética , Álcool Feniletílico/análogos & derivados , Disponibilidade Biológica , Células CACO-2 , Células Hep G2 , Humanos , Hidrólise , Modelos Biológicos , Álcool Feniletílico/metabolismo , Álcool Feniletílico/farmacocinéticaRESUMO
Tyrosol is considered a potential antioxidant; however, little is known regarding the pharmacokinetics of its metabolites. To study the pharmacokinetics of tyrosol-derived metabolites after oral administration of a single dose of tyrosol, we attempted to identify tyrosol metabolites in rat plasma by using ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Two tyrosol metabolites (M1 and M2) were detected in the plasma. M1 was identified as tyrosol-4-sulfate (T4S) with an [M - H](-) ion at m/z 217. While M2 showed an [M - H](-) ion at m/z 151.0, its metabolite was not identified. Pharmacokinetic analysis of T4S and M2 showed rapid uptake after oral administration of tyrosol within 1 h. The metabolites were rapidly distributed in most organs and tissues and eliminated within 4 h. The greatest T4S deposition by tissue weight was observed in the liver, followed by the kidney and spleen, while M2 was most concentrated in the kidney followed by the liver and spleen. These findings indicate that T4S and M2 were distributed mainly in tissues with an abundant blood supply and were rapidly excreted in urine.
Assuntos
Antioxidantes/farmacocinética , Álcool Feniletílico/análogos & derivados , Administração Oral , Animais , Antioxidantes/administração & dosagem , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida , Masculino , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/farmacocinética , Ratos , Espectrometria de Massas em Tandem , Distribuição TecidualRESUMO
Topical chemotherapy is the application of cancer drugs directly onto the skin, which has become a standard treatment for basal cell carcinoma. Due to the promising results in the treatment of skin cancer, topical chemotherapy has recently been applied to breast cancer patients because some breast cancer tissues are only superficial. Hydroxytyrosol, a phenolic compound from olives that is present in high amounts in Hidrox(®) olive extract, has been shown to have a protective effect on normal cells and selective antitumor activities on cancerous cells. The aims of the present study were to develop an alginate bilayer film containing Hidrox(®) and to investigate its potential use as a topical chemotherapeutic agent. Alginate films were characterized for swelling and for physical, thermal, rheological, and mechanical properties. Drug content uniformity and in vitro drug release tests were also investigated. The alginate bilayer films containing Hidrox(®), HB2, showed controlled release of hydroxytyrosol at a flux of 0.094±0.009 mg/cm(2)/h. The results of the cytotoxic assay showed that the HB2 films were dose-dependent and could significantly reduce the growth of breast cancer cells (MCF-7) at 150 µg/mL for a cell viability of 29.34±4.64%. In conclusion, an alginate bilayer film containing Hidrox(®) can be a potential alternative for topical chemotherapeutic agent for skin and breast cancer treatment.
Assuntos
Alginatos/química , Antineoplásicos Fitogênicos/administração & dosagem , Olea/química , Álcool Feniletílico/análogos & derivados , Administração Cutânea , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada , Relação Dose-Resposta a Droga , Liberação Controlada de Fármacos , Feminino , Ácido Glucurônico/química , Ácidos Hexurônicos/química , Humanos , Células MCF-7 , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/farmacocinética , Álcool Feniletílico/farmacologia , Reologia , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
In this work, we discuss leveraging the Biopharmaceutics Classification System (BCS) in the development of edivoxetine HCl, a selective norepinephrine reuptake inhibitor. First, the biopharmaceutical and in vivo data are presented and discussed. Solubility studies indicate that edivoxetine HCl meets the BCS "highly soluble" criteria. To determine permeability classifications, in vitro intestinal Caco-2 epithelial cell model with and without cyclosporin A (CsA), a common P-glycoprotein (P-gp) inhibitor, were conducted. Pharmacokinetic (PK) data obtained across phase 1 and 2 clinical studies where single and multiple doses range from the lowest to the highest strength are presented. Neither the Caco-2 nor the in vivo data on their own were sufficient to conclusively classify edivoxetine as highly permeable. However, collectively the data were utilized to support high permeability and consequently BCS1 classification of edivoxetine HCl. BCS1 classification was leveraged throughout development to assess the risk associated with not conducting relative bioavailability (RBA) studies and avoiding bioequivalence (BE) studies. Examples are presented where formulation changes were made between phase I (drug in capsule/drug in bottle formulations) and phase II (tablet) trials in addition to phase III (tablet) and commercial (smaller tablet) without having to conduct any in vivo comparability studies. For the first change, BCS was leveraged to avoid conducting a RBA study even before obtaining official BCS classification. For the later change, official BCS1 classification was relied upon to avoid conducting a BE study.
Assuntos
Biofarmácia/classificação , Descoberta de Drogas/métodos , Disponibilidade Biológica , Biofarmácia/métodos , Células CACO-2/metabolismo , Cápsulas , Química Farmacêutica/métodos , Ensaios Clínicos Fase I como Assunto/métodos , Humanos , Absorção Intestinal , Morfolinas/administração & dosagem , Morfolinas/farmacocinética , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/farmacocinética , Solubilidade , ComprimidosRESUMO
AIMS: The natural phenolic oil compound hydroxytyrosol (HTy) is widely studied because of its antioxidant and neuroprotective properties. Nitroderivatives of HTy have been studied in order to evaluate their putative effects on catechol-O-methyltransferase (COMT) activity. MAIN METHODS: To study its effect on dopamine metabolism, nitrohydroxytyrosol and its lipophilic derivatives (nitrohydroxytyrosyl acetate and ethyl nitrohydroxytyrosyl ether), were administered into the rat corpus striatum through a microdialysis probe. Other catechols (HTy and the known COMT inhibitor Ro 41-0960) were also studied for comparison. KEY FINDINGS: The olive oil phenolic compounds (nitroderivatives and HTy) increased extracellular levels of 3,4-dihydroxyphenylacetic acid during the perfusion with similar maximum values to that of Ro 41-0960 when comparing to basal dialysate levels (approximately 140%). None of the compound series produced a decrease in the homovanillic acid extracellular levels below 75%. Among all novel compounds studied, both lipophilic nitrocatechols (nitrohydroxytyrosyl acetate and ethyl nitrohydroxytyrosyl ether) showed a long-acting effect over time once the perfusion through the microdialysis probe ended. SIGNIFICANCE: In accordance with the actual design of novel COMT inhibitors with a long profile, our results suggest a certain influence of the side chain substituent on the COMT activity that could provide new lipophilic COMT inhibitors.
Assuntos
Antioxidantes , Inibidores de Catecol O-Metiltransferase , Corpo Estriado/metabolismo , Dopamina/metabolismo , Microdiálise , Álcool Feniletílico/análogos & derivados , Animais , Antioxidantes/farmacocinética , Antioxidantes/farmacologia , Benzofenonas/farmacologia , Catecol O-Metiltransferase/metabolismo , Inibidores de Catecol O-Metiltransferase/farmacocinética , Inibidores de Catecol O-Metiltransferase/farmacologia , Masculino , Álcool Feniletílico/farmacocinética , Álcool Feniletílico/farmacologia , Ratos , Ratos WistarRESUMO
Norepinephrine, a neurotransmitter in the autonomic sympathetic nervous system, is deaminated by monoamine oxidase to 3,4-dihydroxyphenylglycol (DHPG). Inhibition of the NE transporter (NET) using DHPG as a biomarker was evaluated using atomoxetine, duloxetine, and edivoxetine as probe NET inhibitors. Pharmacokinetic and pharmacodynamic data were obtained from healthy subjects (n = 160) from 5 clinical trials. An indirect response model was used to describe the relationship between drug plasma concentration and DHPG concentration in plasma and cerebrospinal fluid (CSF). The baseline plasma DHPG concentration (1130-1240 ng/mL) and Imax (33%-37%) were similar for the 3 drugs. The unbound plasma drug IC50 (IC50U ) based on plasma DHPG was 0.973 nM for duloxetine, 0.136 nM for atomoxetine, and 0.041 nM for edivoxetine. The baseline CSF DHPG concentration (1850-2260 ng/mL) was similar for the 3 drugs, but unlike plasma DHPG, the Imax for DHPG was 38% for duloxetine, 53% for atomoxetine, and75% for edivoxetine. The IC50U based on CSF DHPG was 2.72 nM for atomoxetine, 1.22 nM for duloxetine, and 0.794 nM for edivoxetine. These modeling results provide insights into the pharmacology of NET inhibitors and the use of DHPG as a biomarker.
Assuntos
Cloridrato de Atomoxetina/farmacologia , Cloridrato de Duloxetina/farmacologia , Metoxi-Hidroxifenilglicol/análogos & derivados , Morfolinas/farmacologia , Norepinefrina/metabolismo , Álcool Feniletílico/análogos & derivados , Adolescente , Inibidores da Captação Adrenérgica/sangue , Inibidores da Captação Adrenérgica/farmacologia , Adulto , Idoso , Cloridrato de Atomoxetina/sangue , Cloridrato de Atomoxetina/farmacocinética , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Cloridrato de Duloxetina/sangue , Feminino , Humanos , Masculino , Metoxi-Hidroxifenilglicol/sangue , Metoxi-Hidroxifenilglicol/líquido cefalorraquidiano , Metoxi-Hidroxifenilglicol/metabolismo , Pessoa de Meia-Idade , Modelos Biológicos , Morfolinas/sangue , Morfolinas/farmacocinética , Álcool Feniletílico/sangue , Álcool Feniletílico/farmacocinética , Álcool Feniletílico/farmacologia , Adulto JovemRESUMO
The notion that (poly)phenols act as direct free radical scavengers is being challenged by mere chemical and biochemical considerations such as bioavailability and intracellular concentrations. An alternative hypothesis that is gaining considerable traction is that (poly)phenols are processed by the body as xenobiotics via the Keap1/Nrf2/ARE signaling axis, leading to the induction of Phase II enzymes. However, there are no solid human data to confirm this interesting supposition. In this study, we tested the activities of hydroxytyrosol (HT) on Phase II enzymes' expression in a double-blind, randomized, placebo-controlled study. We tested two HT doses, i.e. 5 and 25mg/d, vs. placebo following a Latin square design. We report that HT is well tolerated but does not significantly modify Phase II enzyme expression in peripheral blood mononuclear cells. Moreover, we were unable to record significant effects on a variety of surrogate markers of cardiovascular disease such as lipid profile and inflammation and oxidation markers. Available evidence indicates that the "hormesis hypothesis" that (poly)phenols activate Phase II enzymes requires solid human confirmation that might be provided by future trials. This study is registered at ClinicalTrials.gov (identifier: NCT02273622).
Assuntos
Antioxidantes/farmacologia , Ativação Enzimática/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Fígado/efeitos dos fármacos , Álcool Feniletílico/análogos & derivados , Adulto , Antioxidantes/farmacocinética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Ativação Enzimática/genética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/enzimologia , Fígado/enzimologia , Desintoxicação Metabólica Fase II , Álcool Feniletílico/farmacocinética , Álcool Feniletílico/farmacologia , Adulto JovemRESUMO
The phenolic anti-oxidant 3-hydroxytyrosol (HT) is a major constituent of olives and olive oil. Published data showed it was negative in the Ames test at concentrations up to 5 µL per plate, but did induce chromosomal aberrations in human lymphocytes. HIDROX, an olive extract containing approximately 2.4% HT, was reported as both positive and equivocal in an Ames test in different papers from the same laboratory. Negative results for micronucleus induction in vivo in both an acute study and as part of a 90-day rat toxicity study were also reported for HIDROX. Given the widespread use and consumption of olives, olive oil and olive extracts, it was important to obtain more data. Here we confirm that pure HT, and an olive extract containing 15% HT, both induced micronuclei in cultured cells in vitro, but show that these responses were either due to high levels of cytotoxicity or to reaction of HT with culture medium components to produce hydrogen peroxide. Another extract (H40) containing 40% HT also induced micronuclei in vitro, probably via the same mechanism. However, both extracts were negative in robust Ames tests. The 15% HT formulated extract did not induce micronuclei in rat bone marrow after 4 weeks of dosing up to 561 mg HT/kg/day. H40 produced increased rat bone marrow micronucleus frequencies at 250 and 500 mg HT/kg/day in a 90-day toxicity study, but the results were questionable for various reasons. However, when two different batches of this extract were tested in acute micronucleus studies at doses up to 2000 mg HT/kg, giving plasma exposures that exceeded those in the 90-day study, negative results were obtained. Based on weight of evidence it is concluded that the olive extracts tested are not genotoxic at high doses in vivo, and any genotoxic risks for human consumers are negligible.