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1.
Food Chem ; 303: 125351, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31466027

RESUMO

The ability of vegetables to inhibit methylmercury absorption was verified, with the aim of lowering the mercury level in cultured fish. Vegetable juice was obtained from 17 varieties of commercial vegetables. A test solution containing 1 µg/g methylmercury, 10% vegetable juice, and 90% physiological saline (v/v) was introduced into the intestinal tract of red sea bream, and the mercury absorption rate was measured. A significant inhibitory effect was observed for green pepper, burdock, and red shiso, mainly in the fraction with a molecular weight >3 kDa. Frozen storage for one month did not affect the inhibitory effect of green pepper; however, the inhibitory effect of frozen burdock and red shiso were destroyed after one week and one month, respectively. During one month of storage in frozen conditions, the inhibitory effect of green pepper was observed in fractions larger than 100 kDa. Molecular weight distribution of the effective fraction varied among the vegetables.


Assuntos
Sucos de Frutas e Vegetais/análise , Absorção Intestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Mercúrio/metabolismo , Dourada , Animais , Mercúrio/química , Mercúrio/toxicidade , Alimentos Marinhos/análise
2.
Carbohydr Polym ; 227: 115337, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31590880

RESUMO

A gel delivery system was developed in the present work using whey protein isolate and lotus root amylopectin via regulating pH. The texture, thermodynamics, rheology and microstructure of gels were evaluated. Results showed that pH at 7.0 induced a more compact and stable gel structure than other pH. The composite gel formed at pH 7.0 was accordingly employed to encapsulate vitamin D3. Results exhibited that the encapsulation of composite gel of whey protein isolate and lotus root amylopectin could enhance the storage stability of vitamin D3 and protect vitamin D3 from photochemical degradation. Moreover, this encapsulation could control the release of vitamin D3 in simulated intestinal fluid. Animal experiments exhibited that the bioavailability was significantly increased after vitamin D3 was encapsulated by the composite gel. This work indicated that the whey protein isolate-lotus root amylopectin gel is a good delivery system to improve the stability and bioavailability of vitamin D3.


Assuntos
Amilopectina/administração & dosagem , Colecalciferol/administração & dosagem , Sistemas de Liberação de Medicamentos , Vitaminas/administração & dosagem , Proteínas do Soro do Leite/administração & dosagem , Amilopectina/química , Amilopectina/farmacocinética , Animais , Disponibilidade Biológica , Colecalciferol/química , Colecalciferol/farmacocinética , Estabilidade de Medicamentos , Géis , Absorção Intestinal/efeitos dos fármacos , Lotus , Masculino , Camundongos Endogâmicos C57BL , Raízes de Plantas , Vitaminas/química , Vitaminas/farmacocinética , Proteínas do Soro do Leite/química , Proteínas do Soro do Leite/farmacocinética
3.
Toxicol Lett ; 318: 86-91, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31669099

RESUMO

Proton pump inhibitors (PPIs) have been used worldwide to treat gastrointestinal disorders. A recent study showed that long-term use of PPIs caused iron deficiency; however, it is unclear whether PPIs affect iron metabolism directly. We investigated the effect of PPIs on the peptide hepcidin, an important iron regulatory hormone. First, we used the FDA Adverse Event Reporting System database and analyzed the influence of PPIs. We found that PPIs, as well as H2 blockers, increased the odds ratio of iron-deficient anemia. Next, HepG2 cells were used to examine the action of PPIs and H2 blockers on hepcidin. PPIs augmented hepcidin expression, while H2 blockers did not. In fact, the PPI omeprazole increased hepcidin secretion, and omeprazole-induced hepcidin upregulation was inhibited by gene silencing or the pharmacological inhibition of the aryl hydrocarbon receptor. In mouse experiments, omeprazole also increased hepatic hepcidin mRNA expression and blood hepcidin levels. In mice treated with omeprazole, protein levels of duodenal and splenic ferroportin decreased. Taken together, PPIs directly affect iron metabolism by suppressing iron absorption through the inhibition of duodenal ferroportin via hepcidin upregulation. These findings provide a new insight into the molecular mechanism of PPI-induced iron deficiency.


Assuntos
Anemia Ferropriva/induzido quimicamente , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Duodeno/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepcidinas/metabolismo , Absorção Intestinal/efeitos dos fármacos , Ferro/sangue , Inibidores da Bomba de Prótons/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Anemia Ferropriva/sangue , Anemia Ferropriva/fisiopatologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Transporte de Cátions/metabolismo , Duodeno/metabolismo , Duodeno/fisiopatologia , Células Hep G2 , Hepatócitos/metabolismo , Antagonistas dos Receptores Histamínicos H2/toxicidade , Humanos , Ferro/deficiência , Masculino , Camundongos Endogâmicos C57BL , Receptores de Hidrocarboneto Arílico/genética
4.
BMC Complement Altern Med ; 19(1): 337, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31775739

RESUMO

BACKGROUND: Tong-Xie-Yao-Fang (TXYF) has been shown to be effective in diarrhoea-predominant irritable bowel syndrome (IBS-D) patients. However, the underlying mechanism remains to be clarified. The aim of this study was to investigate the efficacy and related mechanisms of TXYF in an IBS-D rat model. METHODS: The IBS-D rat model was established with 4% acetic acid and evaluated by haematoxylin-eosin (HE) staining. Then, IBS-D rats were divided into control, TXYF and rifaximin groups and treated intragastrically with normal saline, TXYF and rifaximin, respectively, for 14 days. The following indicators were measured before and after treatment: defecation frequency, faecal water content (FWC) and colorectal distension (CRD). Histopathological changes in the distal colon were observed after treatment. The expression of OCLN and ZO1 in the distal colon of IBS-D rats reflected the intestinal mucosal permeability, as measured by qRT-PCR, western blot, and enzyme-linked immunosorbent assays (ELISAs). The NF-κB and Notch signalling pathways and inflammation-related factors were investigated. RESULTS: After treatment with TXYF, the defecation frequency, FWC and CRD were significantly lower than those in the model group (P < 0.05). HE staining showed that colonic epithelial cells (CECs) in the IBS-D rats displayed significant oedema, impaired intestinal mucosal integrity and an increased influx of inflammatory cells. A significant reduction in granulocyte and CEC oedema was observed after the administration of TXYF and rifaximin compared to that of the model group and blank group (P < 0.05). TXYF significantly upregulated the expression of OCLN and ZO-1 and downregulated inflammation-related factors (IL-6, IL-1ß, and TNF-α and the chemokine KC) in IBS-D rats compared to those in the model group rats (P < 0.05). In terms of the NF-κB and Notch signalling pathways, the expression of NICD, p-ERK, Hes-1 and p-P65 decreased significantly in the TXYF and rifaximin groups, while the expression of ATOH1 increased significantly compared to that in the model group (P < 0.05). CONCLUSION: TXYF can effectively improve intestinal permeability and enhance intestinal mucosal barrier function, which may be related to inhibition of the inflammatory cascade and the NF-κB and Notch signalling pathways.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Absorção Intestinal/efeitos dos fármacos , Síndrome do Intestino Irritável/metabolismo , NF-kappa B/metabolismo , Receptores Notch/metabolismo , Animais , Citocinas/metabolismo , Diarreia , Modelos Animais de Doenças , Feminino , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Síndrome do Intestino Irritável/patologia , Masculino , Ratos , Transdução de Sinais/efeitos dos fármacos
5.
AAPS PharmSciTech ; 20(8): 321, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31650430

RESUMO

Combined dissolution and permeation systems are designed to simultaneously assess the dissolution of a pharmaceutical dosage form and the permeation of dissolved drugs therefrom. However, there were still some limitations on predicting the possible absorption rate-limiting steps and improving the in vitro-in vivo correlation (IVIVC) of a complete dosage form. In this study, the modified biorelevant media with some solubilizers and pH modifiers were integrated into the drug dissolution/absorption simulating system (DDASS). Indapamide, a poorly soluble compound (pKa = 8.8), was selected to validate the applicability of the modified biorelevant media. The elution and permeation dynamics of indapamide were investigated by using appropriate solubilizing agents in the DDASS. The absorption behaviors were analyzed after oral administration of indapamide in beagle dogs. The absorption rate-limiting steps and IVIVCs were predicted from the dissolution-permeation-absorption dynamic parameters. As a result, the absorption fraction of indapamide in the FaSSIFmod of DDASS was estimated to be approximately 100%, in accordance with its high permeability. The ratios of permeation rate to elution rate were 2.55 and 3.34 for the immediate- and sustained-release tablets of indapamide, respectively, suggesting a dissolution rate-limiting absorption for indapamine. In addition, point-to-point correlations were established between in vitro elution and in vivo absorption by the nonlinear and linear regression analysis ways (r > 0.85). The findings indicate that DDASS is a promising technique to develop improved IVIVCs of a complete dosage form, and the FaSSIFmod is suitable to predict the possible absorption rate-limiting steps of poorly soluble drugs in DDASS.


Assuntos
Liberação Controlada de Fármacos , Indapamida/administração & dosagem , Indapamida/metabolismo , Absorção Intestinal/efeitos dos fármacos , Administração Oral , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/metabolismo , Cães , Composição de Medicamentos , Avaliação Pré-Clínica de Medicamentos/métodos , Previsões , Absorção Intestinal/fisiologia , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Solubilidade , Comprimidos/administração & dosagem , Comprimidos/química , Comprimidos/farmacocinética
6.
Int J Nanomedicine ; 14: 7743-7758, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571874

RESUMO

Purpose: Peptide drugs have been used in therapy various diseases. However, the poor bioavailability of peptide drugs for oral administration has limited their clinical applications, on account of the acidic environment and digestive enzymes inside the human gastrointestinal tract. To enhance stability in the human gastrointestinal tract, bioavailability, and targeted drug delivery of peptide drugs through oral administration, a vitamin B12-modified amphiphilic sodium alginate derivative (CSAD-VB12) was synthesized. Materials and methods: A vitamin B12-modified amphiphilic sodium alginate derivative (CSAD-VB12) was synthesized via the N,N'-dicyclohexylcarbodiimide active method at room temperature, and then characterized using FTIR and 1H NMR spectroscopy. Insulin was used as a model peptide drug and the insulin-loaded CSAD-VB12 (CSAD-VB12/insulin) nanoparticles with negative zeta potentials were prepared in PBS (pH=7.4). Scanning electron microscopy was used to observe CSAD-VB12/insulin as spherical nanoparticles. The CSAD-VB12 derivatives and CSAD-VB12/insulin nanoparticles displayed nontoxicity towards the human colon adenocarcinoma (Caco-2) cells by CCK-8 test. Caco-2 cell model was used to measure the apparent permeability (Papp) of insulin, CSAD/insulin and CSAD-VB12/insulin. Furthermore, confocal was used to confirm the endocytosis of intestinal enterocytes. Type 1 diabetes mice were used to evaluate the intestinal absorption and retention effect of test nanoparticles. Results: They were observed as spherical nanoparticles in the size of 30-50 nm. The CSAD-VB12 derivatives and CSAD-VB12/insulin nanoparticles displayed nontoxicity towards the human colon adenocarcinoma (Caco-2) cells. Comparing with insulin and the CSAD/insulin nanoparticles, the CSAD-VB12/insulin nanoparticles exhibited higher permeation ability through intestinal enterocytes in the Caco-2 cell model. Oral administration of the CSAD-VB12/insulin nanoparticles to Type 1 diabetic mice yields higher intestinal retention effect, targeted absorption, and outstanding efficacy. Conclusion: CSAD-VB12 derivatives enhance the small intestinal absorption efficacy and retention of peptide by oral administration, which indicated that it could be a promising candidate for oral peptide delivery in the prospective clinical application.


Assuntos
Alginatos/química , Sistemas de Liberação de Medicamentos , Peptídeos/administração & dosagem , Preparações Farmacêuticas/administração & dosagem , Vitamina B 12/química , Administração Oral , Alginatos/síntese química , Animais , Células CACO-2 , Morte Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Feminino , Humanos , Insulina/administração & dosagem , Insulina/farmacologia , Insulina/uso terapêutico , Absorção Intestinal/efeitos dos fármacos , Masculino , Camundongos , Nanopartículas/química , Nanopartículas/ultraestrutura , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Espectroscopia de Prótons por Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier , Vitamina B 12/síntese química
7.
Eur J Pharm Biopharm ; 145: 76-84, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31639417

RESUMO

Oral drug delivery is a preferred administration route due to its low cost, high patient compliance and fewer adverse events compared to intravenous administration. However, many pharmaceuticals suffer from poor solubility and low oral bioavailability. One major factor that contributes to low bioavailability are efflux transporters which prevent drug absorption through intestinal epithelial cells. P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are two important efflux transporters in the intestine functioning to prevent toxic materials from entering systemic circulation. However, due to its broad substrate specificity, P-gp limits the absorption of many therapeutics, including chemotherapeutics and antibacterial agents. Methods to inhibit P-gp with competitive inhibitors have not been clinically successful. Here, we show that micron scale devices (microdevices) made from a commonly used biomaterial, polyethylene glycol (PEG), inhibit P-gp through a biosimilar mucus in Caco-2 cells and that transporter function is restored when the microdevices are removed. Microdevices were shown to inhibit P-gp mediated transport of calcein AM, doxorubicin, and rhodamine 123 (R123) and BCRP mediated transport of BODIPY-FL-prazosin. When in contact with Caco-2 cells, microdevices decrease the cell surface amount of P-gp without affecting the passive transport. Moreover, there was an increase in mucosal to serosal transport of R123 with microdevices in an ex-vivo mouse model and increased absorption in vivo. This biomaterial-based approach to inhibit efflux transporters can be applied to a range of drug delivery systems and allows for a nonpharmacologic method to increase intestinal drug absorption while limiting toxic effects.


Assuntos
Transporte Biológico/efeitos dos fármacos , Hidrogéis/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Disponibilidade Biológica , Compostos de Boro/metabolismo , Células CACO-2 , Linhagem Celular Tumoral , Humanos , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Polietilenoglicóis/química , Prazosina/análogos & derivados , Prazosina/metabolismo , Rodamina 123/metabolismo , Solubilidade/efeitos dos fármacos
8.
BMC Complement Altern Med ; 19(1): 242, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488210

RESUMO

BACKGROUND: Cyanidin-3-rutinoside (C3R), a naturally occurring anthocyanin, possesses anti-oxidant, anti-hyperglycemic, anti-glycation and cardioprotective properties. However, its mechanisms responsible for anti-hyperlipidemic activity have not been fully identified. The aim of the study was to investigate the lipid-lowering mechanisms of C3R through inhibition of lipid digestion and absorption in vitro. METHODS: The inhibitory activity of C3R against pancreatic lipase and cholesterol esterase was evaluated using enzymatic fluorometric and enzymatic colorimetric assays, respectively. An enzyme kinetic study using Michaelis-Menten and the derived Lineweaver-Burk plot was performed to understand the possible types of inhibition. The formation of cholesterol micelles was determined using the cholesterol assay kit. The bile acid binding was measured using the colorimetric assay. The NBD cholesterol uptake in Caco-2 cells was determined using fluorometric assay. The mRNA expression of cholesterol transporter (Niemann-Pick C1-like 1) was determined by RT-PCR. RESULTS: The results showed that C3R was a mixed-type competitive inhibitor of pancreatic lipase with the IC50 value of 59.4 ± 1.41 µM. Furthermore, C3R (0.125-1 mM) inhibited pancreatic cholesterol esterase about 5-18%. In addition, C3R inhibited the formation of cholesterol micelles and bound to primary and secondary bile acid. In Caco-2 cells, C3R (12.5-100 µM) exhibited a significant reduction in cholesterol uptake in both free cholesterol (17-41%) and mixed micelles (20-30%). Finally, C3R (100 µM) was able to suppress mRNA expression of NPC1L1 in Caco-2 cells after 24 h incubation. CONCLUSIONS: The present findings suggest that C3R acts as a lipid-lowering agent through inhibition of lipid digestion and absorption.


Assuntos
Antocianinas/farmacologia , Inibidores Enzimáticos/farmacologia , Absorção Intestinal/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Animais , Antocianinas/química , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Colesterol/química , Colesterol/metabolismo , Inibidores Enzimáticos/química , Humanos , Cinética , Esterol Esterase/antagonistas & inibidores , Esterol Esterase/química , Esterol Esterase/metabolismo , Suínos
9.
Toxicol Lett ; 316: 109-118, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31472180

RESUMO

Lithocholic acid (LCA) is both a secondary bile acid and a vitamin D receptor (VDR) ligand. The VDR is activated by 1,25-dihydroxy vitamin D3 and plays an important role in maintaining integrity of the intestinal mucosal barrier. LCA can also substitute for vitamin D to carry out the in vivo functions of vitamin D. However, it is unclear whether activation of the VDR by LCA affects mucosal barrier function. In the present study, we researched the protective effect of LCA on tumor necrosis factor-alpha (TNF-α)-induced intestinal epithelial barrier dysfunction in Caco-2 cells of the human epithelial intestinal adenocarcinoma cell line. Caco-2 cell monolayers were pretreated with LCA and then exposed to 100 ng/mL TNF-α. The results showed that LCA alleviated the decrease in transepithelial electrical resistance and the increase in FITC-Dextran flux induced by TNF-α. LCA ameliorated the TNF-α-induced decrease in protein expression and distribution of ZO-1, E-cadherin, Occludin, and Claudin-1, which are tight junction markers. Additionally, the LCA treatment effectively counteracted TNF-α-mediated downregulation of silent information regulator 1 (SIRT1), nuclear factor erythroid2-related factor 2 (Nrf2), and heme oxygenase-1, which are related to oxidative stress. Increases in NF-κB p-p65 and p-IκB-α induced by TNF-α were significantly inhibited by LCA. Considering all these, the present study indicates that LCA has a significant protective effect on TNF-α-induced injury of intestinal barrier function through the VDR and suggests that suppressing NF-κB signaling and activating the SIRT1/Nrf2 pathway might be one of the mechanisms underlying the protective effect of LCA.


Assuntos
Células Epiteliais/efeitos dos fármacos , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Ácido Litocólico/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Receptores de Calcitriol/agonistas , Sirtuína 1/metabolismo , Fator de Necrose Tumoral alfa/toxicidade , Células CACO-2 , Citoproteção , Impedância Elétrica , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Permeabilidade , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Junções Íntimas/patologia
10.
Eur J Pharm Biopharm ; 143: 98-105, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31425857

RESUMO

Oral delivery of peptides is challenging due to their low uptake through the small intestinal epithelium. Tight junctions, connecting the enterocytes, impede permeability, often necessitating the use of permeation enhancers in the formulation. Loading of peptide and permeation enhancer into micro-scale devices, such as microcontainers, can potentially confine the effective absorptive area through unidirectional release and thereby enhance absorption. This concept is investigated by in vitro permeation studies of insulin across Caco-2 cell and Caco-2/HT29-MTX-E12 co-culture monolayers mimicking the intestinal absorption barrier. The importance of proximity between the microcontainers and the barrier is assessed, by keeping the amounts of insulin and sodium caprate fixed throughout all experiments, while collectively orienting the unidirectional release towards the cell monolayers. Increasing the distance is observed to have a negative effect on insulin permeation matching a one-phase exponential decay function, while no difference in insulin transport is observed between Caco-2 and co-culture monolayers. Although there are no signs of cytotoxicity caused by the microcontainer material, reversible cell deterioration, as a consequence of high local concentrations of sodium caprate, becomes evident upon qualitative assessment of the cell monolayers. These results both suggest a potential of increasing oral bioavailability of peptides by the use of microcontainers, while simultaneously visualising the ability of regaining monolayer integrity upon local permeation enhancer induced toxicity.


Assuntos
Insulina/administração & dosagem , Insulina/química , Permeabilidade/efeitos dos fármacos , Administração Oral , Disponibilidade Biológica , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Linhagem Celular Tumoral , Técnicas de Cocultura/métodos , Humanos , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Peptídeos/administração & dosagem , Peptídeos/química , Junções Íntimas/metabolismo
11.
Int J Pharm ; 569: 118567, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31352051

RESUMO

The aim of this research was to formulate a novel nano-micellar complex carrier with intrinsically enhanced intestinal permeability for rosuvastatin calcium (RSV); as a model of BCS class III active pharmaceutical ingredients (APIs). The model drug is used primarily for treating hypercholesterolemia. Three phospholipid types with different degrees of saturation were chosen for the study. The saturation degree of the phospholipids was calculated accurately by proton NMR. A D-optimal statistical design was utilized to correlate the saturation degree of the phospholipids with the physico-chemical characteristics of the prepared nano-micellar carrier. The nature of the interaction between the phospholipids and the model drug was studied by proton NMR, photon correlation spectroscopy (PCS) and transmission electron microscopy (TEM). Molecular docking and molecular dynamics simulations were performed to understand the formation mechanism of the complex micelles on a molecular level. The results demonstrated that the interaction of the hydrophilic drug molecule with the polar head of a saturated phospholipid induces an intramolecular self-coiling of phospholipid saturated acyl chain leading to a structural transformation from a two-tailed cylindrical configuration into a one-tailed, surfactant-like configuration owing to the flexibility of the saturated chains. This transformation leads to the construction of a novel nano-micellar structure in which the drug has lower water solubility but higher lipophilicity than in traditional micelles. Permeability studies conducted on Caco-2 cells demonstrated that the novel nano-micellar carrier had superior permeability to that of the un-complexed hydrophilic drug. The optimized nano-micellar formulation showed significantly (P < 0.5) superior bioavailability in rats to that of the aqueous drug solution in terms of both the rate and extent of drug absorption. Overall, the results confirmed that the formation of the phospholipid nano-micellar complex increased the permeability of the hydrophilic BCS class III drug and converted it to a class BCS I drug by a simple and effective formulation technique.


Assuntos
Portadores de Fármacos , Micelas , Fosfolipídeos , Animais , Disponibilidade Biológica , Células CACO-2 , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Humanos , Absorção Intestinal/efeitos dos fármacos , Masculino , Simulação de Acoplamento Molecular , Permeabilidade/efeitos dos fármacos , Fosfolipídeos/administração & dosagem , Fosfolipídeos/química , Fosfolipídeos/farmacocinética , Ratos Wistar
12.
Int J Pharm ; 568: 118529, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31323368

RESUMO

Rapamycin as a novel macrolide immunosuppressive agent has been commonly used in organ transplantation owing to its stronger immunosuppressive effect, non-nephrotoxicity and lower side effect. However its drawbacks of low bioavailability and big individual difference remain to be improved in clinical application. Here rapamycin loaded TPGS-Lecithins-Zein nanoparticles (RTLZ-NPs) with core-shell structure were prepared by the phase separation method. The RTLZ-NPs were approximately 190.3 nm in size, with PDI and zeta potential about 0.256 and -19.71 mV respectively. Drug entrapment and loading achieved were about 86.64 and 25.73% respectively. Meanwhile RTLZ-NPs exhibited favorable enzymolysis resistance abilities in gastrointestinal environments and enhanced uptake in Caco-2 cells. The optimum absorption sites of rapamycin in the intestine were duodenum and jejunum as single-pass intestinal perfusion assay. Upon also considering the results of Caco-2 cell assay, it could be speculated that the transport of rapamycin in vivo involved active transport as well as P-glycoprotein (P-gp) based efflux. Finally, the relative oral bioavailability of RTLZ-NPS was 4.33 fold higher than free rapamycin in SD rat. Altogether the designed nanoparticles can be an efficient oral delivery strategy for rapamycin analogues to prevent the attacks from destructive enzymes, reduce cell efflux, increase cell uptake, and then enhance the oral bioavailability.


Assuntos
Portadores de Fármacos/administração & dosagem , Lecitinas/administração & dosagem , Nanopartículas/administração & dosagem , Sirolimo/administração & dosagem , Vitamina E/administração & dosagem , Zeína/administração & dosagem , Administração Oral , Animais , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/administração & dosagem , Cumarínicos/química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Humanos , Absorção Intestinal/efeitos dos fármacos , Lecitinas/química , Lecitinas/farmacocinética , Masculino , Nanopartículas/química , Ratos Sprague-Dawley , Sirolimo/química , Sirolimo/farmacocinética , Tiazóis/administração & dosagem , Tiazóis/química , Vitamina E/química , Vitamina E/farmacocinética , Zeína/química , Zeína/farmacocinética
13.
J Anim Sci ; 97(9): 3938-3946, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31292635

RESUMO

The present study compared the net intestinal absorption of zinc (Zn) and copper (Cu) after meals containing different dietary ratios among these trace elements. Ten 46-kg pigs were used in a cross-over design to assess the 10-h net portal-drained viscera (PDV) flux of serum Cu and Zn after ingestion of boluses containing ZnSO4 and CuSO4 in different Zn:Cu ratios (mg:mg): 120:20; 200:20; 120:8; and 200:8. Arterial Zn concentrations peaked within the first hour post-meal and responses were greater with 200 (0.9 to 1.8 mg/L) than with 120 mg (0.9 to 1.6 mg/L) of dietary Zn (dietary Zn × time, P = 0.05). Net PDV flux of Zn was greater (P = 0.02) with 200 than with 120 mg of dietary Zn and tended to be greater (P = 0.10) with 20 than with 8 mg of dietary Cu. The cumulative PDV appearance of Zn (% of dietary intake) was greater with 120 than 200 mg of dietary Zn from 8 h post-meal (P ≤ 0.04) and with 20 than 8 mg of dietary Cu from 7 h post-meal (P ≤ 0.05). At the end of the postprandial period (10 h), estimated PDV appearance of Zn was 16.0%, 18.4%, 12.0%, and 15.3% of Zn intake for 120:8, 120:20, 200:8, and 200:20 ratios, respectively. For Cu, irrespective of treatment, arterial values varied (P < 0.01) by less than 5% across postmeal times. Net PDV flux was not affected by treatments (P ≥ 0.12), but the value for ratio 120:20 was different from zero (P = 0.03). There was an interaction dietary Zn × dietary Cu on cumulative PDV appearance of Cu (% of dietary intake) at 30 min post-meal (P = 0.04) and thereafter at 3 h post-meal (P = 0.04). For the whole postprandial period (10 h), estimated PDV appearance of Cu was 61.9%, 42.1%, -17.1%, and 23.6% of Cu intake for 120:8, 120:20, 200:8, and 200:20 ratios, respectively. In conclusion, the present dietary amounts and ratios of Zn and Cu can affect the metabolic availability of both trace minerals for pigs. Ratios with 120 mg of dietary Zn maximized the postintestinal availability of both Zn and Cu.


Assuntos
Cobre/metabolismo , Suplementos Nutricionais/análise , Suínos/fisiologia , Oligoelementos/metabolismo , Zinco/metabolismo , Animais , Dieta/veterinária , Feminino , Absorção Intestinal/efeitos dos fármacos , Fígado/metabolismo , Estado Nutricional , Período Pós-Prandial
14.
Eur J Pharm Biopharm ; 142: 411-420, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31306749

RESUMO

Pharmaceutical excipients in drug products are defined as pharmacologically inactive and are integral constituents of all types of oral dosage forms. However, some excipients may increase drug absorption by interacting with the mucosal membrane. If the strategy is to use an excipient with a potential to affect the processes determining the rate and/or extent of the intestinal drug absorption, it is defined as an absorption-modifying excipients (AME). These pharmaceutical excipients may act as AMEs, depending on the amounts applied, and accordingly influence bioequivalence assessment of innovative and generic drug products, as well as enable oral delivery of peptides and oligonucleotides. This review discusses the mechanisms by which AMEs increase drug absorption, and especially permeation step. The focus is on the most recent data regarding how AMEs can be evaluated in preclinical models, with an emphasis on in situ and in vivo intestinal absorption models. The in vivo predictive value of these models is reviewed for five factors of clinical relevance for the intestinal absorption performance: (a) effect and response rate of AMEs, (b) mucosal exposure time and intestinal transit of AMEs, (c) intraluminal AME dilution and prandial state, (d) mucosal recovery and safety, and (e) variability in the effects of the AMEs. We argue that any preclinical investigations of AMEs that fail to consider these processes will ultimately be of limited clinical value and add little to our understanding of how excipients affect intestinal drug absorption.


Assuntos
Excipientes/química , Absorção Intestinal/efeitos dos fármacos , Preparações Farmacêuticas/química , Animais , Humanos , Mucosa Intestinal/metabolismo , Equivalência Terapêutica
15.
Eur J Pharm Biopharm ; 142: 387-395, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31306752

RESUMO

Oral administration of drug products is the preferred administration route. In recent decades there has been an increase in drug candidates with low solubility and/or low permeability. To increase the possibility of oral administration for the poorly permeating drugs, the use of absorption modifying excipients (AMEs) has been proposed. These types of AMEs may also affect the regulatory assessment of a novel drug delivery system if they affect the absorption of a drug from any of the four BCS classes. The effects of AMEs have previously been investigated in various animal models, including the single-pass intestinal perfusion (SPIP) in rats. To further improve the biorelevance and the in vivo predictiveness of the SPIP model, four compounds (atenolol, enalaprilat, ketoprofen, metoprolol) were perfused in fasted or fed state simulated intestinal fluid (FaSSIF or FeSSIF) together with the AMEs N-acetyl-cysteine, caprate, or sodium dodecyl sulfate. For the highly soluble and poorly permeating compounds enalaprilat and atenolol (BCS class III), the flux was increased the most by the addition of SDS in both FaSSIF and FeSSIF. For ketoprofen (BCS class II), the flux decreased in the presence of all AMEs in at least one of the perfusion media. The flux of metoprolol (BCS class I) was not affected by any of the excipients in none of simulated prandial states. The changes in magnitude in the absorption of the compounds were in general smaller in FeSSIF than in FaSSIF. This may be explained by a reduced free concentration AMEs in FeSSIF. Further, the results in FeSSIF were similar to those from intrajejunal bolus administration in rat in a previous study. This suggests that the biorelevance of the SPIP method may be increased when investigating the effects of AMEs, by the addition of intraluminal constituents representative to fasted and/or fed state to the inlet perfusate.


Assuntos
Excipientes/química , Jejum/metabolismo , Absorção Intestinal/efeitos dos fármacos , Jejuno/metabolismo , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Líquidos Corporais/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/fisiologia , Masculino , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Wistar , Dodecilsulfato de Sódio/química , Solubilidade/efeitos dos fármacos
16.
Eur J Pharm Biopharm ; 142: 258-264, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31276759

RESUMO

The effect of drug load and digestion on the solubilization and absorption of fenofibrate in self-nanoemulsifying drug delivery system (SNEDDS) was assessed in a pharmacokinetic study in rats and in an in vitro lipolysis model. SNEDDS containing fenofibrate at 75% of equilibrium solubility (Seq), a super-saturated SNEDDS (super-SNEDDS) containing fenofibrate at 150% of Seq and a super-SNEDDS suspension containing fenofibrate at 100% of Seq and an additional 50% Seq fenofibrate suspended (150% of Seq in total) were used. To assess the effect of lipid digestion on fenofibrate absorption in rats and fenofibrate solubilization during in vitro lipolysis, the lipase inhibitor orlistat was added at 1% (w/w) to the SNEDDS, resulting in six different SNEDDS: SNEDDS, super-SNEDDS and super-SNEDDS suspension with and without orlistat 1% (w/w). In vivo, super-SNEDDS had a higher Cmax and AUC0-30h compared to SNEDDS and super-SNEDDS suspension, both with and without orlistat. While orlistat did not affect fenofibrate absorption in SNEDDS and super-SNEDDS, an increase of Tmax and AUC0-30h for super-SNEDDS suspension was found when orlistat was present. During in vitro lipolysis, the addition of orlistat decreased digestion and lowered drug precipitation. Super-SNEDDS showed significantly increased absorption in rats compared to SNEDDS and super-SNEDDS suspension and the inhibition of digestion resulted in prolonged and increased absorption for the super-SNEDDS suspension.


Assuntos
Fenofibrato/administração & dosagem , Fenofibrato/metabolismo , Administração Oral , Animais , Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Emulsões/farmacocinética , Absorção Intestinal/efeitos dos fármacos , Lipase/metabolismo , Lipólise/efeitos dos fármacos , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/metabolismo , Ratos , Ratos Sprague-Dawley , Solubilidade/efeitos dos fármacos , Suspensões/administração & dosagem , Suspensões/farmacocinética
17.
Food Funct ; 10(7): 4381-4395, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31282516

RESUMO

In this work, fucoxanthin-oleic acid-protein complexes were constructed to improve the dispersibility and intestinal absorption of fucoxanthin in water. The in vivo absorption/antioxidant capacity was evaluated using a mouse model, and the binding processes were investigated using multi-spectroscopic methods and molecular docking. Results showed that the oleic acid-protein delivery system dramatically improved the absorption of fucoxanthin mainly in its original form. When the molar ratio of oleic acid to bovine serum albumin (BSA) was 4 : 1, the plasma response level of fucoxanthin at 4 h could reach 91.25% that of the pure soybean oil delivery system (336.9 pg mL-1vs. 369.2 pmol mL-1). Furthermore, the loading capacity of BSA to fucoxanthin was increased 5 times when oleic acid acted as a protein ligand. Fucoxanthin, oleic acid and BSA can form complexes with good water dispersibility (transmittance nearly 90% and particle size 265 nm) at the molar ratio of 5 : 4 : 1. Spectral analysis and molecular docking indicated that oleic acid and fucoxanthin have different binding domains in BSA and that fucoxanthin can bind to the hydrophobic cavity of BSA in a static manner. After administration of fucoxanthin-oleic acid-BSA complexes for 15 days in mice, only fucoxanthinol accumulation was discovered in eyes and the ocular antioxidant capability increased by 71.02%. These results suggest that the oleic acid-protein delivery system may be useful in facilitating the application of fat-soluble active substances to hydrophilic food systems.


Assuntos
Olho/efeitos dos fármacos , Absorção Intestinal/efeitos dos fármacos , Ácido Oleico/farmacologia , Água/química , Xantofilas/farmacologia , Animais , Antioxidantes , Digestão , Feminino , Tecnologia de Alimentos , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Camundongos , Camundongos Endogâmicos ICR , Modelos Animais , Simulação de Acoplamento Molecular , Tamanho da Partícula , Soroalbumina Bovina/química , Óleo de Soja , Xantofilas/sangue , Xantofilas/química , beta Caroteno/análogos & derivados
18.
Eur J Pharm Biopharm ; 141: 191-209, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31150808

RESUMO

Oral bioavailability of poorly water soluble (BCS II) drugs like danazol can be minimal without the necessary formulation strategies. Availability of in vitro physicochemical and in vivo pharmacokinetic studies can be valuable when designing these strategies but cannot reveal the drug-formulation-gastrointestinal physiology interplay that impact the successful optimization of intestinal solubilization and resulting oral drug absorption. In silico mechanistic oral drug absorption models can serve as a tool for providing this important perspective and for integrating information generated across various in vivo and in vitro studies. In this work, we detail the development and application of the Simcyp canine ADAM model to nine danazol oral formulations and compare the model predictions to caninein vivo pharmacokinetic data from published literature. The application of this mechanistic approach revealed insights suggesting: (1) complete danazol solubilization in vitro may lead to an over-estimation of oral bioavailability when predictions are not corrected for the in vivo conditions promoting gut luminal precipitation; (2) some solubilizing excipients can influence intestinal physiology in a manner that may reduce danazol absorption; (3) danazol-formulation-luminal bile salts interplay can result in the formation of mixed micelles that negatively impact danazol intestinal permeability; and (4) the magnitude of danazol bioavailability enhancement associated with the use of solubilizing agents can be affected by the presence of saturable gut metabolism that can lead to concentration-dependent differences in its influence in vivo formulation behaviour at high versus low doses.


Assuntos
Danazol/farmacocinética , Jejum/metabolismo , Mucosa Intestinal/metabolismo , Administração Oral , Animais , Ácidos e Sais Biliares/metabolismo , Disponibilidade Biológica , Química Farmacêutica/métodos , Cães , Excipientes/química , Absorção Intestinal/efeitos dos fármacos , Intestinos , Modelos Biológicos , Permeabilidade/efeitos dos fármacos , Fenômenos Físicos , Solubilidade/efeitos dos fármacos
19.
World J Gastroenterol ; 25(20): 2450-2462, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31171889

RESUMO

BACKGROUND: Trimethylamine N-oxide (TMAO) has been shown to be involved in cardiovascular disease (CVD). However, its role in nonalcoholic steatohepatitis (NASH) is unknown. AIM: To determine the effect of TMAO on the progression of NASH. METHODS: A rat model was induced by 16-wk high-fat high-cholesterol (HFHC) diet feeding and TMAO was administrated by daily oral gavage for 8 wk. RESULTS: Oral TMAO intervention attenuated HFHC diet-induced steatohepatitis in rats. Histological evaluation showed that TMAO treatment significantly alleviated lobular inflammation and hepatocyte ballooning in the livers of rats fed a HFHC diet. Serum levels of alanine aminotransferase and aspartate aminotransferase were also decreased by TMAO treatment. Moreover, hepatic endoplasmic reticulum (ER) stress and cell death were mitigated in HFHC diet-fed TMAO-treated rats. Hepatic and serum levels of cholesterol were both decreased by TMAO treatment in rats fed a HFHC diet. Furthermore, the expression levels of intestinal cholesterol transporters were detected. Interestingly, cholesterol influx-related Niemann-Pick C1-like 1 was downregulated and cholesterol efflux-related ABCG5/8 were upregulated by TMAO treatment in the small intestine. Gut microbiota analysis showed that TMAO could alter the gut microbial profile and restore the diversity of gut flora. CONCLUSION: These data suggest that TMAO may modulate the gut microbiota, inhibit intestinal cholesterol absorption, and ameliorate hepatic ER stress and cell death under cholesterol overload, thereby attenuating HFHC diet-induced steatohepatitis in rats. Further studies are needed to evaluate the influence on CVD and define the safe does of TMAO treatment.


Assuntos
Fígado/efeitos dos fármacos , Metilaminas/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Administração Oral , Animais , Colesterol na Dieta/efeitos adversos , Colesterol na Dieta/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
20.
Mar Drugs ; 17(6)2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31181804

RESUMO

Zinc-binding peptides from oyster (Crassostrea gigas) have potential effects on zinc supplementation. The aim of this study was to prepare efficient zinc-binding peptides from oyster-modified hydrolysates by adding exogenous glutamate according to the plastein reaction and to further explore the zinc absorption mechanism of the peptide-zinc complex (MZ). The optimum conditions for the plastein reaction were as follows: pH 5.0, 40 °C, substrate concentration of 40%, pepsin dosage of 500 U/g, reaction time of 3 h and l-[1-13C]glutamate concentration of 10 mg/mL. The results of 13C isotope labelling suggested that the addition of l-[1-13C]glutamate contributed to the increase in the zinc-binding capacity of the peptide. The hydrophobic interaction was the main mechanism of action of the plastein reaction. Ultraviolet spectra and scanning electronic microscopy (SEM) revealed that the zinc-binding peptide could bind with zinc and form MZ. Furthermore, MZ could significantly enhance zinc bioavailability in the presence of phytic acid, compared to the commonly used ZnSO4. Additionally, MZ significantly promoted the intestinal absorption of zinc mainly through two pathways, the zinc ion channel and the small peptide transport pathway. Our work attempted to increase the understanding of the zinc absorption mechanism of MZ and to support the potential application of MZ as a supplementary medicine.


Assuntos
Técnicas de Química Analítica/métodos , Absorção Intestinal/efeitos dos fármacos , Ostreidae/química , Peptídeos/química , Peptídeos/farmacologia , Zinco/química , Zinco/metabolismo , Animais , Disponibilidade Biológica , Quelantes/química , Hidrolisados de Proteína/química
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