RESUMEN
Oral administration of peptide represents a promising delivery route, however, it is hindered by the harsh gastrointestinal environment, leading to low in vivo absorption. In this study, auto-adaptive protein corona-AT 1002-cationic liposomes (Pc-AT-CLs) are constructed with the characteristic of hydrophilic and electrically neutral surface properties for the encapsulation of liraglutide. BSA protein corona is used to coat AT-CLs reducing the adherence of mucus, and may fall off after penetrating the mucus layer. Transmucus transport experiment demonstrated that the mucus penetration amount of Pc-AT-CLs are 1.45 times that of AT-CLs. After penetrating the mucus layer, AT-CLs complete transmembrane transport by the dual action of AT and cationic surface properties. Transmembrane transport experiment demonstrated that the apparent permeability coefficient (Papp) of AT-CLs is 2.03 times that of CLs. In vivo tests demonstrated that Pc-AT-CLs exhibited a significant hypoglycemic effect and enhanced the relative bioavailability comparing to free liraglutide. Pc-AT-CLs protect liraglutide from degradation, facilitate its absorption, and ultimately improve its oral bioavailability.
Asunto(s)
Sistemas de Liberación de Medicamentos , Hipoglucemiantes , Liposomas , Liraglutida , Moco , Animales , Liraglutida/administración & dosificación , Liraglutida/farmacocinética , Liraglutida/farmacología , Moco/metabolismo , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/química , Humanos , Disponibilidad Biológica , Administración Oral , Masculino , Ratas Sprague-Dawley , Ratas , Absorción Intestinal/efectos de los fármacosRESUMEN
Efficient telmisartan delivery for hypertension management requires the incorporation of meglumine and/or sodium hydroxide as an alkalizer in the formulation. Long-term use of powerful alkalis with formulation as part of chronic therapy can cause metabolic alkalosis, ulcers, diarrhea, and body pain. Here, we aimed to design a telmisartan formulation without alkalizers. Telmisartan properties were tailor-made by microfluidizer-based physical modification. After microfluidization, telmisartan nanosuspension was lyophilized to obtain telmisartan premix powder. The optimized telmisartan nanosuspension had an average particle size of 579.85 ± 32.14 nm. The lyophilized premix was characterized by FT-IR, DSC, and PXRD analysis to ensure its physicochemical characteristics. The solubility analysis of premix showed 2.2 times, 2.3 times, and 6 times solubility improvement in 0.1 N HCl, phosphate buffer pH 7.5, and pH 6.8 compared to pure telmisartan. A 3D in-vitro Caco-2 model was developed to compare apparent permeability of API and powder premix. It showed that the powder premix was more permeable than pure API. The tablet formulation prepared from the telmisartan premix showed a dissolution profile comparable to that of the marketed formulation. The technique present herein can be used as a platform technology for solubility and permeability improvement of similar classes of molecules.
Asunto(s)
Tamaño de la Partícula , Permeabilidad , Solubilidad , Telmisartán , Telmisartán/administración & dosificación , Telmisartán/farmacocinética , Telmisartán/química , Humanos , Células CACO-2 , Composición de Medicamentos/métodos , Absorción Intestinal/efectos de los fármacos , Polvos/química , Concentración de Iones de Hidrógeno , Nanopartículas/química , Química Farmacéutica/métodos , Liberación de Fármacos , Funcion de la Barrera IntestinalRESUMEN
Modifications to the small intestine and liver are known to occur during the symptomatic disease period of amyotrophic lateral sclerosis (ALS), a member of the motor neuron disease (MND) family of neurodegenerative disorders. How these modifications impact on oral absorption and pharmacokinetics of drugs remains unknown. In this study, model drugs representing different mechanisms of intestinal transport (caffeine for passive diffusion, digoxin for P-glycoprotein efflux, and sulfasalazine for breast cancer resistance protein efflux) were administered via oral gavage to postnatal day 114-120 male and female SOD1G93A mice (model of familial ALS) and wild-type (WT) littermates. Samples of blood, brain and spinal cord were taken at either 15, 30, 60 or 180 min after administration. In addition, the in vivo gastric emptying of 70 kDa fluorescein isothiocyanate-dextran (FITC-dextran) and the ex vivo intestinal permeability of caffeine were assessed. The area under the plasma concentration-time curves (AUCplasma) of digoxin and sulfasalazine were not significantly different between SOD1G93A and WT mice for both sexes. However, the AUCplasma of caffeine was significantly lower (female: 0.79-fold, male: 0.76-fold) in SOD1G93A compared to WT mice, which was associated with lower AUCbrain (female: 0.76-fold, male: 0.80-fold) and AUCspinal cord (female: 0.81-fold, male: 0.82-fold). The AUCstomach of caffeine was significantly higher (female: 1.5-fold, male: 1.9-fold) in SOD1G93A compared to WT mice, suggesting reduced gastric emptying in SOD1G93A mice. In addition, there was a significant reduction in gastric emptying of FITC-dextran (0.66-fold) and ex vivo intestinal permeability of caffeine (0.52-fold) in male SOD1G93A compared to WT mice. Reduced systemic and brain/spinal cord exposure of caffeine in SOD1G93A mice may therefore result from alterations to gastric emptying and small intestinal permeability. Specific dosing requirements may therefore be required for certain medicines in ALS to ensure that they remain in a safe and effective concentration range.
Asunto(s)
Esclerosis Amiotrófica Lateral , Encéfalo , Cafeína , Modelos Animales de Enfermedad , Ratones Transgénicos , Médula Espinal , Animales , Cafeína/administración & dosificación , Cafeína/farmacocinética , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/metabolismo , Médula Espinal/metabolismo , Médula Espinal/efectos de los fármacos , Masculino , Femenino , Ratones , Administración Oral , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Digoxina/farmacocinética , Digoxina/administración & dosificación , Sulfasalazina/farmacocinética , Sulfasalazina/administración & dosificación , Absorción Intestinal/efectos de los fármacos , Absorción Intestinal/fisiologíaRESUMEN
Diacylglycerol O-acyltransferase 1 (DGAT1) is a key enzyme for fat absorption step in the enterocytes. We previously reported that DGAT1 inhibition increased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in corn oil-loaded rats via protein kinase C (PKC) activation. In the present study, we investigated the mechanism with respect to the morphology and permeability of the small intestine, focusing on PKC function, and found that shortening of the intestinal villi and a decrease in the number of tdT-mediated dUTP-biotin nick-end labeling-positive cells in the tips of the villi were observed in the jejunum of DGAT1 inhibitor-treated rats loaded with corn oil. These results suggested that the tips of the villi were shed into the intestinal lumen. Next, fluorescein isothiocyanate-dextran, 110â¯kDa (FD-110) was administered intraduodenally to DGAT1 inhibitor-treated rats loaded with corn oil and we found that plasma FD-110 concentrations increased, indicating that the intestinal permeability to molecules with a molecular weight of approximately 110,000 (e.g., ALT and AST) increased. Taken together, the present results suggested that DGAT1 inhibitor-treatment in combination with corn oil causes ALT and AST to leak from the enterocytes into the blood by shedding the tips of the intestinal villi and increasing intestinal permeability.
Asunto(s)
Alanina Transaminasa , Aspartato Aminotransferasas , Aceite de Maíz , Diacilglicerol O-Acetiltransferasa , Mucosa Intestinal , Permeabilidad , Animales , Alanina Transaminasa/sangre , Masculino , Aspartato Aminotransferasas/sangre , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Diacilglicerol O-Acetiltransferasa/metabolismo , Permeabilidad/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Ratas , Dextranos , Proteína Quinasa C/metabolismo , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Fluoresceína-5-Isotiocianato/análogos & derivados , Yeyuno/efectos de los fármacos , Yeyuno/metabolismo , Absorción Intestinal/efectos de los fármacos , Ratas Sprague-Dawley , Ratas Wistar , Funcion de la Barrera IntestinalRESUMEN
The goal of the current study was to formulate and examine the potential of poly (lactic-co-glycolic acid) (PLGA) as carriers to facilitate the targeted administration of edoxaban tosylate monohydrate (ETM). ETM-PLGA-NPs were effectively formulated using the nanoprecipitation technique. Particle size, drug entrapment percentage, zeta potential, assessment of intestinal absorption, FT-IR, SEM, drug dissolution behavior, and histopathology investigations were used to describe ETM-PLGA-NPs. The produced NPs had a roughly spherical shape with a particle size of 99.85 d.nm, a PDI of 0.478, and a zeta potential of 38.5 mV with a maximum drug entrapment of 82.1 %. FTIR measurements showed that the drug's chemical stability remained intact after preapred into nanoparticles. In vitro drug release behavior followed the Higuchi model and revealed an early burst release of 30 % and persistent drug release of 78 % from optimized NPs for up to 120 hrs. According to in vitro data, a 1:10 ratio of ETM to PLGA provided longer-lasting ETM release and improved encapsulation efficiency. Images captured with an inverted fluorescent microscope exhibited that NPs may both greatly increase the amount of ETM accumulated in the intestinal tract and make it easier for ETM to enter the membrane beneath the cells of the intestines. The study found that using PLGA nanoparticles to encapsulate the ETM resulted in longer circulation duration (aPTT, PT, TT). In vivo investigations found that nanoparticles encapsulated had no negative impact on hematological parameters, lung, liver, or kidney tissues. All things considered, the NPs are a potential delivery method to increase the oral absorption and antithrombotic activity of ETM.
Asunto(s)
Portadores de Fármacos , Liberación de Fármacos , Nanopartículas , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Piridinas , Tiazoles , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Nanopartículas/química , Animales , Portadores de Fármacos/química , Tiazoles/farmacocinética , Tiazoles/administración & dosificación , Tiazoles/química , Piridinas/administración & dosificación , Piridinas/farmacocinética , Piridinas/química , Ratas , Masculino , Ácido Láctico/química , Absorción Intestinal/efectos de los fármacos , Ácido Poliglicólico/química , Sistemas de Liberación de Medicamentos/métodos , Inhibidores del Factor Xa/administración & dosificación , Inhibidores del Factor Xa/farmacocinética , Ratas Wistar , Distribución TisularRESUMEN
High blood pressure is a major risk factor for cardiovascular disease. Our previous study confirmed that daily intake of casein hydrolysate that contained Met-Lys-Pro (MKP) can safely lower mildly elevated blood pressure. The present study aimed to evaluate the intestinal absorption differences between peptide MKP as a casein hydrolysate and synthetic MKP alone using Caco-2 cells and human iPS cell-derived small intestinal epithelial cells (hiSIECs). MKP was transported intact through Caco-2 cells and hiSIECs with permeability coefficient (Papp) values of 0.57 ± 0.14 × 10-7 and 1.03 ± 0.44 × 10-7 cm/s, respectively. This difference in Papp suggests differences in the tight junction strength and peptidase activity of each cell. Moreover, the transepithelial transport and residual ratio of intact MKP after adding casein hydrolysate containing MKP was significantly higher than that after adding synthetic MKP alone, suggesting that other peptides in casein hydrolysate suppressed MKP degradation and increased itsãtransport. These findings suggest that hiSIECs could be useful for predicting the human intestinal absorption of bioactive peptides; ingesting MKP as a casein hydrolysate may also improve MKP bioavailability.
Asunto(s)
Caseínas , Células Epiteliales , Absorción Intestinal , Intestino Delgado , Humanos , Caseínas/metabolismo , Células CACO-2 , Absorción Intestinal/efectos de los fármacos , Intestino Delgado/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Disponibilidad Biológica , PermeabilidadRESUMEN
Magnesium, an essential mineral for various physiological functions, is subject to tight regulation within the body. Understanding its absorption across epithelial cell monolayers is crucial for optimizing dietary magnesium intake and therapeutic strategies. The Caco-2 monolayer model, widely recognized for its relevance to the human intestinal epithelium, provides a suitable platform for this investigation. This protocol covers the step-by-step procedures for the cultivation of Caco-2 monolayer preparation of transwell systems. It provides guidance on the setup of magnesium transport experiments, which involve the application of magnesium salts to the apical side of the Caco-2 monolayer and monitoring their transport to the basolateral side.
Asunto(s)
Mucosa Intestinal , Magnesio , Humanos , Células CACO-2 , Mucosa Intestinal/metabolismo , Magnesio/metabolismo , Permeabilidad , Transporte Biológico , Técnicas de Cultivo de Célula/métodos , Absorción Intestinal/efectos de los fármacos , Sales (Química)/metabolismoRESUMEN
Some glycoside drugs can be transported through intestinal glucose transporters (IGTs). The surfactants used in oral drug preparations can affect the function of transporter proteins. This study aimed to investigate the effect of commonly used surfactants, Poloxamer 188 and Tween 80, on the drug transport capacity of IGTs. Previous studies have shown that gastrodin is the optimal drug substrate for IGTs. Gastrodin was used as a probe drug to evaluate the effect of these two surfactants on intestinal absorption in SD rats through pharmacokinetic and in situ single-pass intestinal perfusion. Then, the effects of the two surfactants on the expression of glucose transporters and tight-junction proteins were examined using RT-PCR and western blotting. Additionally, the effect of surfactants on intestinal permeability was evaluated through hematoxylin-eosin staining. The results found that all experimental for Poloxamer 188 (0.5%, 2.0% and 8.0%) and Tween 80 (0.1% and 2.0%) were not significantly different from those of the blank group. However, the AUC(0-∞) of gastrodin increased by approximately 32% when 0.5% Tween 80 was used. The changes in IGT expression correlated with the intestinal absorption of gastrodin. A significant increase in the expression of IGTs was observed at 0.5% Tween 80. In conclusion, Poloxamer 188 had minimal effect on the drug transport capacity of IGTs within the recommended limits of use. However, the expression of IGTs increased in response to 0.5% Tween 80, which significantly enhanced the drug transport capacity of IGTs. However, 0.1% and 2.0% Tween 80 had no significant effect.
Asunto(s)
Absorción Intestinal , Mucosa Intestinal , Poloxámero , Polisorbatos , Ratas Sprague-Dawley , Tensoactivos , Animales , Poloxámero/farmacología , Polisorbatos/farmacología , Ratas , Absorción Intestinal/efectos de los fármacos , Masculino , Tensoactivos/farmacología , Transporte Biológico/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Glucósidos/farmacologíaRESUMEN
Dynamic in vitro absorption systems and mechanistic absorption modeling via PBPK have both shown promise in predicting human oral absorption, although these efforts have been largely separate; this work aimed to integrate knowledge from these approaches to investigate the oral absorption of a RET inhibitor, pralsetinib, with BCS Class II properties. Tiny-TIM (TIM B.V., Weteringbrugâ, The Netherlands) is a dynamic in vitro model with close simulation of the successive physiological conditions of the human stomach and small intestine. Tiny-TIM runs with pralsetinib were performed at doses of 200 mg and 400 mg under fasting conditions. Mechanistic modeling of absorption was performed in Simcyp V21 (Certara, Manchester, UK). Pralsetinib fasted bioaccessibility in the Tiny-TIM system was 63% at 200 mg and 53% at 400 mg; a 16% reduction at 400 mg was observed under elevated gastric pH. Maximum pralsetinib solubility from the small intestinal compartment in Tiny-TIM directly informed the supersaturation/precipitation model parameters. The PBPK model predicted a similar fraction absorbed at 200 mg and 400 mg, consistent with the dose proportional increases in observed pralsetinib exposure. Integrating dynamic in vitro systems with mechanistic absorption modeling provides a promising approach for understanding and predicting human absorption with challenging low solubility compounds.
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Absorción Intestinal , Modelos Biológicos , Humanos , Absorción Intestinal/efectos de los fármacos , Administración Oral , Solubilidad , Intestino Delgado/metabolismo , Intestino Delgado/efectos de los fármacos , Simulación por ComputadorRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Pudilan Xiaoyan Oral Liquid (PDL) is a proprietary Chinese medicinal preparation approved by the State for treating acute pharyngitis in both adults and children (Approval No. Z20030095). It is worth noting that children exhibit unique physiopathological characteristics compared to adults. However, the in vivo regulatory characteristics of PDL in treating acute pharyngitis in children remain incompletely understood. AIM OF THE STUDY: The differential absorption and metabolism characteristics of the main pharmacological components in PDL in young and adult rats were investigated with a view to providing a reference for preclinical data of PDL in medication for children. MATERIALS AND METHODS: This study utilized UPLC-Q-TOF-MS to investigate the pharmacodynamic material basis of PDL. The focus was on the gastrointestinal digestion and absorption characteristics of organic acid components in PDL (PDL-OAC), known as the primary pharmacodynamic components in this formulation. The research combined in vitro dynamic simulation and a Quadruple single-pass intestinal perfusion model to examine these characteristics. The permeability properties of PDL-OAC were evaluated using an artificial parallel membrane model. Additionally, an acute pharyngitis model was established to evaluate the histopathological condition of the pharynx in young rats using H&E staining. The levels of IL-1ß, TNF-α, IL-6, and IL-10 in blood and pharyngeal tissue homogenates of young rats were quantified using ELISA kits. RESULTS: A total of 91 components were identified in PDL, including 33 organic acids, 24 flavonoids, 14 alkaloids, 5 terpenoids and coumarins, 3 sugars, and 12 amino acids. The PDL-OAC exhibited a significant reduction in IL-1ß, TNF-α, IL-6, and IL-10 levels in the pharyngeal tissues of young rats with acute pharyngitis. Results from dynamic simulation studies of gastrointestinal fluids revealed that the PDL-OAC (Specifically chlorogenic acid (CGA), gallic acid (GA), chicoric acid (CRA), and caffeic acid (CA)) were effectively stabilized in the gastrointestinal fluids of both children and adults in vitro. Young rats, characterized by thinner intestinal walls and higher permeability, efficiently absorbed the four organic acids across the entire intestinal segment. The absorption of CGA, GA, and CRA followed a concentration-dependent pattern, with CGA and GA absorption being influenced by exocytosis. CONCLUSION: The efficacy of the PDL-OAC in treating acute pharyngitis was demonstrated in young rats. The absorption rate of these components was observed to be faster in young rats compared to adult rats, underscoring the need for dedicated studies on the drug's usage in children. This research provides valuable insights for the appropriate clinical use of PDL in pediatric patients.
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Medicamentos Herbarios Chinos , Absorción Intestinal , Ratas Sprague-Dawley , Animales , Medicamentos Herbarios Chinos/farmacocinética , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/farmacología , Masculino , Ratas , Absorción Intestinal/efectos de los fármacos , Administración Oral , Ácidos Cafeicos/farmacocinética , Ácidos Cafeicos/administración & dosificación , Factores de EdadRESUMEN
Colchicine (COL) is known for its ability to inhibit the formation of intestinal chylomicrons and has been utilized as a non-surgical tool to explore drug absorption via the intestinal lymphatics. However, there is limited understanding of its pharmacokinetics and its relationship to effect and toxicity with the doses used. This study aimed to provide comprehensive COL pharmacokinetic data and correlate it with the lymphatic-blocking and toxicological effects of low-doses. Male Sprague-Dawley rats with jugular-vein cannulation (JVC) received 0.1 to 0.5 mg/kg COL via oral, 0.25 mg/kg intraperitoneal, and 0.1 mg/kg intravenous routes, followed by blood and urine sampling for LC-MS/MS analysis. Effects on lipid absorption were assessed in another eight JVC rats receiving peanut oil with and without COL, followed by blood pharmacokinetic and plasma biochemistry analysis. The results revealed that COL exhibited moderate extraction ratio and high volume of distribution, with low oral bioavailability (<8%). About 20 % was recovered in the urine after parenteral dosing. Modest but significant reductions in cholesterol absorption was observed after oral doses of 0.5 mg/kg, accompanied by signs of inflammation and increased liver enzymes persisting for a week. The effect of COL on triglycerides formation was not significant. Despite its use as a non-surgical tool in rats to investigate drug absorption via the lymphatic pathway, COL demonstrated increased levels of liver function enzymes, emphasizing the need for caution and dose optimization in its utilization.
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Disponibilidad Biológica , Quilomicrones , Colchicina , Ratas Sprague-Dawley , Animales , Masculino , Colchicina/farmacocinética , Colchicina/administración & dosificación , Colchicina/toxicidad , Ratas , Quilomicrones/metabolismo , Administración Oral , Absorción Intestinal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Espectrometría de Masas en Tándem/métodos , Aceite de Cacahuete/administración & dosificación , Aceite de Cacahuete/farmacocinética , Aceite de Cacahuete/toxicidad , ColesterolRESUMEN
The therapeutic effects of orally administered nanocarriers depend on their ability to effectively permeate the intestinal mucosa, which is one of the major challenges in oral drug delivery. Microfold cells are specialized enterocytes in the intestinal epithelium known for their high transcytosis abilities. This study aimed to compare and evaluate two targeting approaches using surface modifications of polymer-based nanocarriers, whereas one generally addresses enterocytes, and one is directed explicitly to microfold cells via targeting the sialyl LewisA motif on their surface. We characterized the resulting carriers in terms of size and charge, supplemented by scanning electron microscopy to confirm their structural properties. For predictive biological testing and to assess the intended targeting effect, we implemented two human intestinal in vitro models containing microfold-like cells. Both models were thoroughly characterized prior to permeation studies with the different nanocarriers. Our results demonstrated improved transport for both targeted formulations compared to undecorated carriers in the in vitro models. Notably, there was an enhanced uptake in the presence of microfold-like cells, particularly for the nanocarriers directed by the anti-sialyl LewisA antibody. These findings highlight the potential of microfold cell targeting to improve oral administration of drugs and emphasize the importance of using suitable and well-characterized in vitro models for testing novel drug delivery strategies.
Asunto(s)
Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Mucosa Intestinal , Células M , Nanopartículas , Humanos , Administración Oral , Células CACO-2 , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Enterocitos/metabolismo , Enterocitos/efectos de los fármacos , Absorción Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Células M/metabolismo , Nanopartículas/química , Permeabilidad , Polímeros/químicaRESUMEN
Nalbuphine (NAL) is a κ-agonist/µ-antagonist opioid being developed as an oral extended formulation (ER) for the treatment of chronic cough in idiopathic pulmonary fibrosis and itch in prurigo nodularis. NAL is extensively glucuronidated and likely undergoes enterohepatic recirculation (EHR). The purpose of this work is to develop pharmacokinetic models for NAL absorption and enterohepatic recirculation (EHR). Clinical pharmacokinetic (PK) data sets in healthy subjects from three trials that included IV, oral solution, and ER tablets in fed and fasted state and two published trials were used to parametrize a novel partial differential equation (PDE)-based model, termed "PDE-EHR" model. Experimental inputs included in vitro dissolution and permeability data. The model incorporates a continuous intestinal absorption framework, explicit liver and gall bladder compartments, and compartments for systemic drug disposition. The model was fully PDE-based with well-stirred compartments achieved by rapid diffusion. The PDE-EHR model accurately reproduces NAL concentration-time profiles for all clinical data sets. NAL disposition simulations required inclusion of both parent and glucuronide recirculation. Inclusion of intestinal P-glycoprotein efflux in the simulations suggests that NAL is not expected to be a victim or perpetrator of P-glycoprotein-mediated drug interactions. The PDE-EHR model is a novel tool to predict EHR and food/formulation effects on drug PK. The results strongly suggest that even intravenous dosing studies be conducted in fasted subjects when EHR is suspected. The modeling effort is expected to aid in improved prediction of dosing regimens and drug disposition in patient populations.
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Absorción Intestinal , Nalbufina , Humanos , Absorción Intestinal/fisiología , Absorción Intestinal/efectos de los fármacos , Nalbufina/farmacocinética , Nalbufina/administración & dosificación , Modelos Biológicos , Circulación Enterohepática , Administración Oral , Voluntarios Sanos , Ayuno/metabolismo , Masculino , Adulto , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/administración & dosificaciónRESUMEN
Carthamus tinctorius L. (Safflower) is extensively used as a functional food and herbal medicine, with its application closely associated with hydroxysafflor yellow A (HSYA). However, the low oral bioavailability of HSYA in safflower extract (SFE) limits its health benefits and application. Our study found that co-administration of 250, 330, and 400 mg/kg peach kernel oil (PKO) increased the oral bioavailability of HSYA in SFE by 1.99-, 2.11-, and 2.49-fold, respectively. The enhanced bioavailability is attributed to improved lipid solubility and intestinal permeability of HSYA in SFE due to PKO. PKO is believed to modify membrane fluidity and tight junctions, increase paracellular penetration, and inhibit the expression and function of P-glycoprotein, enhancing the transcellular transport of substrates. These mechanisms suggest that PKO is an effective absorption enhancer. Our findings provide valuable insights for developing functional foods with improved bioavailability.
Asunto(s)
Disponibilidad Biológica , Carthamus tinctorius , Chalcona , Extractos Vegetales , Prunus persica , Quinonas , Chalcona/química , Chalcona/análogos & derivados , Chalcona/farmacología , Extractos Vegetales/química , Extractos Vegetales/administración & dosificación , Extractos Vegetales/metabolismo , Quinonas/química , Quinonas/metabolismo , Carthamus tinctorius/química , Animales , Prunus persica/química , Prunus persica/metabolismo , Humanos , Aceites de Plantas/química , Masculino , Ratas Sprague-Dawley , Ratas , Absorción Intestinal/efectos de los fármacosRESUMEN
The nutritional quality of plant-based meat analogues compared to traditional meat products has been questioned in recent commentary, particularly in relation to protein quality and micronutrient bioavailability. However, the attributes of specific products within this category are unclear. We therefore undertook a comprehensive assessment of the compositional and functional attributes of v2food® (Sydney, Australia) plant-based mince, including an assessment of the effects of reformulation, including the addition of amino acids, ascorbic acid, and different forms of elemental iron. The protein digestibility and protein quality of v2food® plant-based mince were comparable to beef mince in the standardized INFOGEST system, and favourable effects on microbiota composition and short-chain fatty acid (SCFA) production were demonstrated in an in vitro digestion system. The use of ferrous sulphate as an iron source improved in vitro intestinal iron absorption by ~50% in comparison to other forms of iron (p < 0.05), although levels were ~3-fold lower than beef mince, even in the presence of ascorbic acid. In conclusion, the current study identified some favourable nutritional attributes of plant-based v2food® mince, specifically microbiota and SCFA changes, as well as other areas where further reformulation could be considered to further enhance the bioavailability of key nutrients. Further studies to assess the effect of plant-based meat analogues on health measures in vivo will be important to improve knowledge in this area.
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Heces , Microbioma Gastrointestinal , Absorción Intestinal , Humanos , Microbioma Gastrointestinal/fisiología , Heces/microbiología , Heces/química , Absorción Intestinal/efectos de los fármacos , Proteínas en la Dieta/metabolismo , Hierro/metabolismo , Hierro/farmacocinética , Valor Nutritivo , Disponibilidad Biológica , Ácido Ascórbico , Ácidos Grasos Volátiles/metabolismo , Digestión , Compuestos FerrososRESUMEN
Calcium is the most abundant mineral in the human body and is involved in critical physiological and cellular processes. It is essential for the development, maintenance, and integrity of bone tissue throughout life. Identifying new natural food-grade chelating agents to improve calcium uptake is of increasing interest. Casein phosphopeptides (CPPs), highly phosphorylated peptides obtained after enzymatic hydrolysis of caseins, represent promising calcium-chelating candidates. The aim of this study was to investigate, using cell culture models, the ability of a digested milk matrix enriched in CPPs to regulate calcium transport through the intestinal barrier and elucidate the involved mechanisms. To this end, a CPP-preparation underwent in vitro static digestion and was subsequently incubated with an intestinal barrier model to monitor calcium uptake and transport. Our results demonstrated that the digested CPP preparation enhanced the trans-epithelial calcium transport via paracellular pathways and that CPPs, identified by peptidomics, crossed the intestinal barrier in the same time.
Asunto(s)
Calcio , Caseínas , Mucosa Intestinal , Fosfopéptidos , Caseínas/farmacología , Caseínas/metabolismo , Caseínas/química , Fosfopéptidos/farmacología , Fosfopéptidos/metabolismo , Fosfopéptidos/química , Humanos , Calcio/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Células CACO-2 , Transporte Biológico , Animales , Digestión , Absorción Intestinal/efectos de los fármacosRESUMEN
Variances in the biological functions of astaxanthin geometric isomers (i.e., all-E, Z) are related to their intestinal absorption, but the mechanism of isomer absorption mediated by transporters remains unclear. Here, models of in vitro cell overexpression, in situ intestinal perfusion, and in vivo mouse inhibition were employed to investigate the impact of cluster of differentiation 36 (CD36) on the absorption of astaxanthin isomers. Cells overexpressing CD36 notably enhanced the uptake of Z-astaxanthin, particularly the 9-Z-isomer (47.76%). The absorption rate and permeability of Z-astaxanthin surpassed that of the all-E-isomer by the in situ model. Furthermore, the addition of the CD36-specific inhibitor sulfo-N-succinimidyl oleate significantly reduced the absorption of Z-astaxanthin in the mouse duodenum and jejunum, especially the 9-Z-isomer (57.66%). Molecular docking and surface plasmon resonance techniques further validated that 9-Z-astaxanthin binds to more amino acids of CD36 with higher affinity and in a fast-binding, fast-dissociating mode, thus favoring transport. Our findings elucidate, for the first time, the mechanism of the CD36-mediated transmembrane transport of astaxanthin geometric isomers.
Asunto(s)
Antígenos CD36 , Absorción Intestinal , Simulación del Acoplamiento Molecular , Xantófilas , Xantófilas/metabolismo , Xantófilas/química , Animales , Antígenos CD36/metabolismo , Antígenos CD36/genética , Ratones , Absorción Intestinal/efectos de los fármacos , Masculino , Humanos , Isomerismo , Ratones Endogámicos C57BL , Yeyuno/metabolismo , Unión ProteicaRESUMEN
Reformulation with addition of antioxidants is one potential mitigation strategy to prevent or reduce nitrosamine drug substance-related impurities (NDSRIs) in drug products. To explore whether there could be other approaches to demonstrate bioequivalence for a reformulated oral product, which typically needs in vivo bioequivalence studies to support the changes after approval, the effects of antioxidant on the in vitro permeability of BCS III model drug substances were investigated to see whether there could be any potential impact on drug absorption. Six antioxidants were screened and four (ascorbic acid, cysteine, α-tocopherol and propyl gallate) were selected based on their nitrosamine inhibition efficiencies. The study demonstrated that these four antioxidants, at the tested amounts, did not have observable impact on the in vitro permeability of the BCS III model drug substances across Caco-2 cell monolayers in the In Vitro Dissolution Absorption System (IDAS). An in vitro permeability study could be considered as part of one potential bioequivalence bridging approach for reformulated low-risk immediate release solid oral products and oral suspension products. Other factors such as the influence of antioxidants on intestinal transporter activities should be considered where appropriate.
Asunto(s)
Antioxidantes , Permeabilidad , Humanos , Células CACO-2 , Antioxidantes/farmacología , Antioxidantes/farmacocinética , Permeabilidad/efectos de los fármacos , Absorción Intestinal/efectos de los fármacos , Equivalencia Terapéutica , Ácido Ascórbico/farmacología , Preparaciones Farmacéuticas/metabolismo , Preparaciones Farmacéuticas/química , alfa-Tocoferol/farmacología , Solubilidad , Cisteína/química , Administración OralRESUMEN
There are several in vitro systems that enable evaluation of the absorption direction, but there are few quantitative systems that enable easy evaluation of the excretion direction. Enteroids, organoids derived from intestine, have been frozen and passaged for various research. But it is not clear how the freezing and passaging affect the expression and function of transporters. We investigated the effects of passage and cryopreservation of enteroids. We focused on P-gp (P-glycoprotein) and compared the transfer rates of rhodamine 123 (Rh123) into the lumen of enteroids with and without a P-gp inhibitor. mRNA expression levels did not change significantly before and after passage and cryopreservation. Accumulation of Rh123 in the lumen of enteroids was observed. With some P-gp inhibitors, excretion of Rh123 into the lumen of enteroids was inhibited and the nonexcreted Rh123 accumulated in enteroids epithelial cells. The transfer rate of Rh123 into the lumen of enteroids with a P-gp inhibitor was significantly decreased compared to that of without a P-gp inhibitor. Before and after passage and cryopreservation, the transfer rate was almost the same as that of primary cultured enteroids. We succeeded in easily evaluating whether a component is a substrate of P-gp using enteroids.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Criopreservación , Organoides , Rodamina 123 , Rodamina 123/metabolismo , Organoides/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Criopreservación/métodos , Transporte Biológico/fisiología , Animales , Mucosa Intestinal/metabolismo , Humanos , Absorción Intestinal/fisiología , Absorción Intestinal/efectos de los fármacos , Intestinos , RatonesRESUMEN
Purpose: Reducing the first-pass hepatic effect via intestinal lymphatic transport is an effective way to increase the oral absorption of drugs. 2-Monoacylglycerol (2-MAG) as a primary digestive product of dietary lipids triglyceride, can be assembled in chylomicrons and then transported from the intestine into the lymphatic system. Herein, we propose a biomimetic strategy and report a 2-MAG mimetic nanocarrier to target the intestinal lymphatic system via the lipid absorption pathway and improve oral bioavailability. Methods: The 2-MAG mimetic liposomes were designed by covalently bonding serinol (SER) on the surface of liposomes named SER-LPs to simulate the structure of 2-MAG. Dihydroartemisinin (DHA) was chosen as the model drug because of its disadvantages such as poor solubility and high first-pass effect. The endocytosis and exocytosis mechanisms were investigated in Caco-2 cells and Caco-2 cell monolayers. The capacity of intestinal lymphatic transport was evaluated by ex vivo biodistribution and in vivo pharmacokinetic experiments. Results: DHA loaded SER-LPs (SER-LPs-DHA) had a particle size of 70 nm and a desirable entrapment efficiency of 93%. SER-LPs showed sustained release for DHA in the simulated gastrointestinal environment. In vitro cell studies demonstrated that the cellular uptake of SER-LPs primarily relied on the caveolae- rather than clathrin-mediated endocytosis pathway and preferred to integrate into the chylomicron assembly process through the endoplasmic reticulum/Golgi apparatus route. After oral administration, SER-LPs efficiently promoted drug accumulation in mesenteric lymphatic nodes. The oral bioavailability of DHA from SER-LPs was 10.40-fold and 1.17-fold larger than that of free DHA and unmodified liposomes at the same dose, respectively. Conclusion: SER-LPs improved oral bioavailability through efficient intestinal lymphatic transport. These findings of the current study provide a good alternative strategy for oral delivery of drugs with high first-pass hepatic metabolism.