RESUMEN
We previously reported that α-glycosylated naringin (naringin-G), synthesized by enzyme-catalyzed transglycosylation, can enhance the solubility of poorly water-soluble compounds without surface-active property. However, the solubilization mechanism has not been fully elucidated. In this study, the solubilization mechanism of naringin-G was investigated using nuclear magnetic resonance (NMR) spectroscopy, and its application in skin formulations was further investigated. 1H NMR and dynamic light scattering measurements at various concentrations confirmed the self-assembled nanostructures of naringin-G above a critical aggregation concentration of approximately 2.2 mg/mL. Two-dimensional 1H-1H nuclear Overhauser effect spectroscopy and solubility tests revealed that flavone with poor water solubility, could be solubilized in its self-assembled structure with a stoichiometric relationship with naringin-G. When naringin-G was included in the skin formulation, the permeated amount and permeability coefficient (Papp) of flavones improved up to four times with increasing amounts of naringin-G. However, flavone solubilization by adding an excessive amount of naringin-G resulted in a decreased permeated amount and Papp of flavones, indicating the interplay between the apparent solubility and skin permeability of flavones. Naringin-G, which forms a nanoaggregate structure without exhibiting surface-active properties, has the potential to enhance the solubility and skin permeation of poorly water-soluble compounds.
Asunto(s)
Flavanonas , Nanoestructuras , Piel , Solubilidad , Flavanonas/química , Glicosilación , Nanoestructuras/química , Animales , Piel/metabolismo , Absorción Cutánea/efectos de los fármacos , Administración Cutánea , Flavonas/química , Permeabilidad , Espectroscopía de Resonancia Magnética/métodosRESUMEN
Water soluble α-glycosylated rutin (4G-α-D-glucopyranosyl rutin, monoglucosyl rutin, MR) was used in this study to evaluate its ability to reduce abdominal visceral fat (AVF). We conducted a study examining 66 healthy Japanese men and women with a body mass index of ≥23 and <30 kg/m2 for 8 weeks. The subjects were randomly assigned to groups via computer random numbers as follows: MR200 group (MR 200 mg/day), MR400 group (MR 400mg/day), or placebo group. The primary outcome was change in the AVF area after 8 weeks of intervention. The secondary outcomes were effects of MR on total fat and subcutaneous fat of umbilical area, lipid-related markers, and subjective symptoms. The per-protocol set analysis involved 18 subjects in the placebo group (7 males and 11 females), 20 subjects in the MR200 group (8 males and 12 females), and 20 subjects in the MR400 group (8 males and 12 females). AVF area in both the MR200 and MR400 groups was reduced at week 8, with changes from the baseline (week 0) significantly higher than the placebo group. Additionally, the MR400 group reported improved subjective symptoms concerning being "worried about abdominal fat" at week 4 compared with the placebo group. These results indicate that the consumption of MR (200 and 400 mg/day) for 8 weeks reduced AVF. PRACTICAL APPLICATION: Monoglucosyl rutin, an enzymatically modified form of rutin, is a highly stable and water-soluble flavonoid widely used in food and beverages to prevent oxidation. The present clinical study demonstrated that it may improve overall health by reducing abdominal visceral fat.
Asunto(s)
Grasa Abdominal/metabolismo , Grasa Intraabdominal/metabolismo , Rutina/análogos & derivados , Adulto , Anciano , Índice de Masa Corporal , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Rutina/administración & dosificación , Rutina/química , Pérdida de Peso/efectos de los fármacosRESUMEN
The possibility of newly developed α-glycosylated naringin (Naringin-G) as a solubilizing agent was investigated against pranlukast hemihydrate (PLH), a model drug with extremely low water solubility. The physical mixtures (PMs) of PLH/Naringin-G increased the solubility of PLH compared with PLH crystals and PMs with other additives, such as α-glycosylated rutin (Rutin-G) and sodium dodecyl sulfate (SDS). Naringin-G did not decrease the surface tension, whereas SDS showed a surface-active property and critical micelle concentration. The apparent solubility of PLH increased in proportion to the concentration of Naringin-G, and similarly for SDS, indicating that constant amounts of Naringin-G molecules interacted with PLH molecules. There was no change in the Caco-2 cell viability following contact with a high concentration of Naringin-G solution (10% (w/v)). The oral absorption of PLH in a rat animal model was improved when administrated with Naringin-G. The value for the area under plasma concentration-time curve from PMs of PLH/Naringin-G was 2.2 times higher than that from PLH crystals alone. Together, these results suggested that newly synthesized Naringin-G would be a promising solubilizing agent as an alternative to surfactants.
Asunto(s)
Cromonas , Flavanonas , Administración Oral , Animales , Disponibilidad Biológica , Células CACO-2 , Supervivencia Celular/efectos de los fármacos , Cromonas/administración & dosificación , Cromonas/química , Cromonas/farmacocinética , Flavanonas/administración & dosificación , Flavanonas/química , Flavanonas/farmacocinética , Glicosilación , Humanos , Absorción Intestinal , Masculino , Ratas Sprague-Dawley , SolubilidadRESUMEN
We successfully prepared folic acid (FA) nanoparticles with excellent dispersibility and photostability using a combination of bead milling and freeze-drying with transglycosylated naringin (Naringin-G), a newly developed transglycosylated food additive. Poly-vinyl pyrrolidon (PVP) was used for comparison with Naringin-G. Water dispersibility and photostability of the freeze-dried formulations were assessed. The dispersibility and physicochemical properties of nanoparticle formulations were evaluated using dynamic light scattering, powder X-ray diffraction (PXRD), and small-angle X-ray scattering (SAXS). Results indicated that the median particle size of FA in the slurry bead milled with Naringin-G decreased notably with time and fell below 100â¯nm after milling for 300â¯min. Further, FA nanoparticles with Naringin-G were stable without aggregation following re-dispersion of freeze-dried FA formulations in water. Contrarily, the addition of PVP did not prevent the aggregation of FA nanoparticles following re-dispersion of freeze-dried FA formulations. Solid structures of freeze-dried FA formulations with Naringin-G or PVP were assessed using PXRD and SAXS. PXRD patterns of all freeze-dried formulations highlighted broadening and weakening of peaks, indicating a decrease in FA crystallinity following bead milling, regardless of the additive concentration of Naringin-G and PVP. The scattering intensity profiles of FA formulations with PVP dramatically decreased after milling, whereas FA formulations with Naringin-G did not exhibit changes in SAXS patterns. FA formulations with Naringin-G registered faster enhancement in release rate than PVP in pHâ¯1.2 buffer solutions. The release rate of freeze-dried FA formulation with Naringin-G exhibited at least five-fold enhancement when compared to untreated FA. FA formulation with Naringin-G was stable to photodegradation under fluorescent light. Naringin-G prevented photodegradation of FA due to its antioxidant effect and scavenged radicals. These findings indicated that freeze-dried FA formulation with Naringin-G can improve its water-dispersibility and photodegradation due to the effectiveness of Naringin-G as a dispersant and cryoprotectant.
Asunto(s)
Flavanonas/química , Ácido Fólico/química , Nanopartículas/química , Crioprotectores , Estabilidad de Medicamentos , Ácido Fólico/farmacocinética , Liofilización , Tamaño de la Partícula , Procesos FotoquímicosRESUMEN
Hesperidin (HES) is a flavanone glycoside found in citrus peel that contributes to its bitter taste. It has low water solubility and poor oral bioavailability. To improve its solubility and bioavailability, α-monoglucosyl hesperidin (αGH) has been synthesized from HES by transglucosylation using cyclodextrin glucanotransferase. Several reports indicate that αGH significantly decreases body fat, but the underlying molecular mechanism remains unclear. We hypothesized that the antiobesity effects of αGH occur through the induced formation of brown-like adipocytes. The present study verified that dietary αGH induces brown-like adipocytes to form in mouse inguinal white adipose tissue (iWAT), thereby significantly decreasing the weight of white adipose tissue (WAT). Furthermore, dietary αGH significantly induced thermogenesis in iWAT. Dietary αGH also significantly suppressed high-fat-diet-induced WAT accumulation in mice, which may be mediated by brown-like adipocyte formation. These results indicate that dietary αGH induces increased energy expenditure by stimulating the formation of brown-like adipocytes.
Asunto(s)
Adipocitos Marrones/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Hesperidina/química , Hesperidina/farmacología , Adipocitos Marrones/fisiología , Tejido Adiposo Blanco/crecimiento & desarrollo , Animales , Fármacos Antiobesidad , Disponibilidad Biológica , Composición Corporal/efectos de los fármacos , Dieta Alta en Grasa , Glucosiltransferasas/metabolismo , Glicosilación , Masculino , Ratones , Ratones Endogámicos C57BL , Tamaño de los Órganos/efectos de los fármacos , Relación Estructura-Actividad , Termogénesis/efectos de los fármacosRESUMEN
The poor water solubility of rebamipide was enhanced by the mixed micelles of transglycosylated stevia (Stevia-G) and trimethylammonium chloride with varying carbon chain length (C nTAC, n = 14, 16, and 18). Fluorometry, isothermal titration calorimetry (ITC) and dynamic light scattering techniques examined the aggregation properties of Stevia-G and C nTAC. Synergism was found between Stevia-G and C nTAC using the approaches of Clint and Rubingh. The negative interaction parameter (average ßm = -4.17, -5.47, and -7.07) and excess free energy (average ΔG°ex = -2.47, -3.06, and -3.88 kJ mol-1) increased with increasing chain length of C nTAC. The negative B1 values by the Maeda approach suggested that chain-chain interactions contribute to the formation of a mixed micelle. The solubilization of rebamipide in the mixed micelle was evaluated in the term of the molar solubilization ratio (MSR) and partition coefficient ( Km). The Km from the Stevia-G/C16TAC system was highest at a low mole fraction of C nTAC (0.2-0.6). In conclusion, the solubilization of rebamipide was more favorable between Stevia-G and C16TAC, although the stability of the mixed micelle was enhanced by an increase in hydrophobicity of the longer chain lengths used in C nTAC.
Asunto(s)
Alanina/análogos & derivados , Diterpenos de Tipo Kaurano/química , Glucósidos/química , Quinolonas/química , Tensoactivos/química , Alanina/química , Calorimetría , Cationes/química , Dispersión Dinámica de Luz , Fluorometría , Interacciones Hidrofóbicas e Hidrofílicas , Micelas , Solubilidad , TermodinámicaRESUMEN
We designed an off-line combination of HPLC/photodiode array detector (PDA) and 1H-quantitative NMR (1H-qNMR) to estimate the relative molar sensitivity (RMS) of an analyte to a reference standard. The RMS is calculated as follows: a mixture of the analyte and the reference is analyzed using 1H-qNMR and HPLC/PDA. The response ratio of the analyte and the reference obtained by HPLC/PDA is then corrected using the molar ratio obtained by 1H-qNMR. We selected methylparaben (MPB), which is a certified reference material, as the reference standard and hesperidin (Hes) and monoglucosylhesperidin (MGHes) as analytes, and the RMSs of Hes283 nm/MPB255 nm and MGHes283 nm/MPB255 nm were determined as 1.25 and 1.32, respectively. We determined the contents of Hes and MGHes in processed foods by the conventional absolute calibration method and by the internal standard method employing the RMS values with respect to MPB. The differences between the values obtained with the two methods were less than 2.0% for Hes and 3.5% for MGHes.
Asunto(s)
Análisis de los Alimentos/métodos , Manipulación de Alimentos , Hesperidina/análogos & derivados , Hesperidina/análisis , Espectroscopía de Resonancia Magnética/métodos , Calibración , Cromatografía Líquida de Alta Presión/métodos , Parabenos/análisisRESUMEN
OBJECTIVES: We studied the relation between the polymorphism of P-glycoprotein (P-gp) and of breast cancer resistance protein (BCRP), encoded by ABCB1 and ABCG2 genes, respectively, and the pharmacokinetic variability and clinical response during the treatment with sorafenib of hepatocellular carcinoma. METHODS: At the Paul Brousse Hospital in Villejuif, France, 47 consecutive patients with advanced HCC treated with a single agent sorafenib, were enrolled. Sorafenib exposure was measured by its plasma concentration 3 h after oral administration of 400 mg (bid) by liquid chromatography. All enrolled patients were genotyped for ABCB1 (rs2032582; rs1045642) and ABCG2 (rs2231137; rs2231142; rs2622604) by blood genomic DNA extraction and Mass ARRAY genotyping. The clinical response was evaluated after 3months of treatment according to the RECIST criteria. KEY FINDINGS: Significant associations between sorafenib exposure and the studied polymorphisms were observed for ABCB1 3435C>T, ABCG2 34G>A, ABCG2 1143C>T and ABCG2 421C>A, but not for ABCB1 2677G>TA SNP. In heterozygous patients for ABCB1 3435 C>T, ABCG2 34 G>A and ABCG2 1143 C>T polymorphisms were significantly associated with the lowest sorafenib plasma levels. Those patients presented a tendency to have the best clinical evolution. CONCLUSION: Heterozygous forms of the studied polymorphisms could be associated with a better therapeutic response.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/genética , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Proteínas de Neoplasias/genética , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacocinética , Neoplasias de la Mama/tratamiento farmacológico , ADN/genética , Monitoreo de Drogas , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Niacinamida/farmacocinética , Niacinamida/uso terapéutico , Compuestos de Fenilurea/farmacocinética , Polimorfismo Genético/genética , Polimorfismo de Nucleótido Simple/genética , Inhibidores de Proteínas Quinasas/farmacocinética , Sorafenib , Resultado del TratamientoRESUMEN
We report the full assignment of 1H and 13C NMR signals belonging to α-glucosyl rhoifolin (Rhf-G), a novel transglycosylated compound synthesized from a flavone glycoside, rhoifolin, as well as its chemical structure. Furthermore, we report the complete NMR signal assignment for another transglycosylated compound, α-glucosyl rutin (Rutin-G), as the signals corresponding to its sugar moieties had not been identified. Electrospray ionization-mass spectrometry along with multiple NMR methods revealed that Rhf-G possesses three sugar moieties in its chemical structure. The additional glucose was bound directly via a transglycosylation to rhoifolin at position 3a of the sugar moiety. Interestingly, intramolecular hydrogen bonds in the basic Rhf-G and Rutin-G skeletons were confirmed by HMBC experiments. These findings will be helpful for comprehensive NMR studies on transglycosylated compounds in food, cosmetic, and pharmaceutical fields.
Asunto(s)
Disacáridos/química , Flavonoides/química , Glicósidos/química , Rutina/química , Glicosilación , Espectroscopía de Resonancia MagnéticaRESUMEN
In a previous study, we showed that cetuximab, a monoclonal antibody directed towards epidermal growth factor receptor, could inhibit P-glycoprotein (P-gp), an efflux protein of ATP-binding cassette family, and lead to an increased P-gp substrate intracellular concentration. Cetuximab is given with irinotecan to patients with metastasis colorectal cancer who did not respond to irinotecan-based therapy. The mechanism of this successful clinical reversion remains unknown. As irinotecan is a P-gp substrate, we tested here whether cetuximab could modify irinotecan concentration in mice. Therefore, concentrations of irinotecan and of its active metabolite SN-38 were measured by HPLC in plasma and tumour of mice bearing a human colorectal carcinoma xenograft when irinotecan is given orally alone or after a pretreatment with cetuximab. Pharmacokinetic analysis showed no significant modification of irinotecan concentrations but a significant increase (1.7-fold) in SN-38 AUCs in plasma and in tumour after a pretreatment with cetuximab. Those results suggest that cetuximab influence irinotecan distribution into tissues probably due to inhibition of P-gp. As SN-38 is 200-fold more potent than irinotecan, cetuximab could reverse irinotecan resistance by an effect on its active metabolite. Inhibiting SN-38 efflux by P-gp drug transporters in biliary system and tumour can lead to pharmacokinetic modification and a higher anticancer efficacy.