Model Of Intestinal Absorption Research Articles

Disposition of Oral Nalbuphine and Its Metabolites in Healthy Subjects and Subjects with Hepatic Impairment: Preliminary Modeling Results Using a Continuous Intestinal Absorption Model with Enterohepatic Recirculation.

Nalbuphine (NAL) is a mixed κ-agonist/μ-antagonist opioid with extensive first-pass metabolism. A phase 1 open-label study was conducted to characterize the pharmacokinetics (PKs) of NAL and select metabolites following single oral doses of NAL extended-release tablets in subjects with mild, moderate, and severe hepatic impairment (Child-Pugh A, B, and C, respectively) compared to healthy matched subjects. NAL exposures were similar for subjects with mild hepatic impairment as compared to healthy subjects and nearly three-fold and eight-fold higher in subjects with moderate and severe hepatic impairment, respectively. Datasets obtained for healthy, moderate, and severe hepatic impaired groups were modeled with a mechanistic model that incorporated NAL hepatic metabolism and enterohepatic recycling of NAL and its glucuronidated metabolites. The mechanistic model includes a continuous intestinal absorption model linked to semi-physiological liver-gallbladder-compartmental PK models based on partial differential equations (termed the PDE-EHR model). In vitro studies indicated that cytochromes P450 CYP2C9 and CYP2C19 are the major CYPs involved in NAL oxidation, with glucuronidation mainly catalyzed by UGT1A8 and UGT2B7 isozymes. Complex formation and elimination kinetics of NAL and four main metabolites was well predicted by PDE-EHR. The model is expected to improve predictions of drug interactions and complex drug disposition.

A Continuous Intestinal Absorption Model to Predict Drug Enterohepatic Recirculation in Healthy Humans: Nalbuphine as a Model Substrate.

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.

Controlling the Solubility, Release Rate and Permeation of Riluzole with Cyclodextrins.

Riluzole (RLZ), a sodium channel-blocking benzothiazole anticonvulsant BCS class II drug, is very slightly soluble in aqueous medium. To improve aqueous solubility and modulate dissolution rate and membrane permeability, complex formation of RLZ with two cyclodextrin, α-cyclodextrin (α-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD), was studied. The stability constants demonstrated a greater affinity of SBE-β-CD towards RLZ compared to α-CD. A solubility growth of 1.7-fold and 3.7-fold with α-CD and SBE-β-CD, respectively, was detected in the solutions of 1% cyclodextrins and accompanied by the permeability reduction. For 1% CD solutions, several biopolymers (1% w/v) were tested for the membrane permeability under static conditions. The synergistic positive effect of α-CD and polymer on the solubility accompanied by unchanged permeability was revealed in RLZ/α-CD/PG, RLZ/α-CD/PEG400, and RLZ/α-CD/PEG1000 systems. Solid RLZ/CD complexes were prepared. Dynamic dissolution/permeation experiments for the solid samples disclosed the characteristic features of the release processes and permeation rate through different artificial membranes. The maximal permeation rate was determined across the hydrophilic semi-permeable cellulose membrane followed by the lipophilic PermeaPad barrier (model of intestinal and buccal absorption) and polydimethylsiloxane-polycarbonate membrane (simulating transdermal delivery way). Different mode of the permeation between the membranes was estimated and discussed.

Insights into multi-component digestion and antioxidant release from plant protein-seaweed-based Maillard conjugate-MRP systems

Maillard conjugation to modify protein functionality results in the formation of a protein-polysaccharide complex. The resultant conjugate mixture is rich in different Maillard reaction products (MRP) and unreacted components. The investigation pertaining to the digestion and intestinal fate of these components is challenging due to the multitude of effects and interactions between different components. This study attempts to understand gastrointestinal behaviour and diffusion/release patterns of different components from a complex system made of the amaranth-Gracilaria seaweed system. Data acquired from in-vitro INFOGEST protocol and intestinal dialysis absorption model were used to investigate the amino acid release and antioxidant diffusion during different phases of digestion. The analysis suggests a significant improvement in the radical scavenging capacity of overall antioxidants released from the conjugate-MRP system compared to that of amaranth protein alone based on different antioxidant assays (DPPH, FRAP, ICred) during each stage of digestion. The permeability and overall intestinal absorption ratio of antioxidants through a dialysis membrane shows an improvement of up to 55 % compared to that of the plant protein. Moreover, amino acid and phyto-compounds release patterns of the conjugate-MRP system exhibit selective shielding effects towards the gastric phase, which can potentially be investigated for targeted release of bioactive compounds.

Microencapsulation of broccoli sulforaphane using whey and pea protein: in vitro dynamic gastrointestinal digestion and intestinal absorption by Caco-2-HT29-MTX-E12 cells.

Sulforaphane, an organosulfur phytochemical, has been demonstrated to have significant anticancer potential in both in vitro and in vivo studies, exhibiting mechanisms of action that include inducing apoptosis, inhibiting cell proliferation, and modulating key signalling pathways involved in cancer development. However, its instability presents a major obstacle to its clinical application due to its limited bioavailability. This study aimed to improve the stability and thus the bioavailability of sulforaphane from broccoli by microencapsulation with whey (BW) and pea protein (BP) by freeze-drying. BW and BP were characterised by particle size measurement, colour, infrared spectroscopy, scanning electron microscopy, thermogravimetry, and differential scanning calorimetry. Dynamic in vitro gastrointestinal digestion was performed to measure sulforaphane bioaccessibility, in BP, BW and dried broccoli. A Caco-2-HT29-MTX-E12 intestinal absorption model was used to measure sulforaphane bioavailability. The in vitro dynamic gastrointestinal digestion revealed that sulforaphane bioaccessibility of BW was significantly higher (67.7 ± 1.2%) than BP (19.0 ± 2.2%) and dried broccoli (19.6 ± 10.4%) (p < 0.01). In addition, sulforaphane bioavailability of BW was also significantly greater (54.4 ± 4.0%) in comparison to BP (9.6 ± 1.2%) and dried broccoli (15.8 ± 2.2%) (p < 0.01). Microencapsulation of broccoli sulforaphane with whey protein significantly improved its in vitro bioaccessibility and bioavailability. This suggests that whey protein isolate could be a promising wall material to protect and stabilise sulforaphane for enhanced bioactivity and applications (such as nutraceutical formulations).

Contribution of the Dynamic Intestinal Absorption Model (Diamod) to the Development of a Patient-Centric Drug Formulation.

Compound X is a weak basic drug targeting the early stages of Parkinson's disease, for which a theoretical risk assessment has indicated that elevated gastric pH conditions could potentially result in reduced plasma concentrations. Different in vitro dissolution methodologies varying in level of complexity and a physiologically based pharmacokinetic (PBPK) absorption model demonstrated that the dissolution, solubility, and intestinal absorption of compound X was indeed reduced under elevated gastric pH conditions. These observations were confirmed in a crossover pharmacokinetic study in Beagle dogs. As a result, the development of a formulation resulting in robust performance that is not sensitive to the exposed gastric pH levels is of crucial importance. The dynamic intestinal absorption MODel (Diamod), an advanced in vitro gastrointestinal transfer tool that allows to study the gastrointestinal dissolution and interconnected permeation of drugs, was selected as an in vitro tool for the formulation optimization activities given its promising predictive capacity and its capability to generate insights into the mechanisms driving formulation performance. Different pH-modifiers were screened for their potential to mitigate the pH-effect by decreasing the microenvironmental pH at the dissolution surface. Finally, an optimized formulation containing a clinically relevant dose of the drug and a functional amount of the selected pH-modifier was evaluated for its performance in the Diamod. This monolayer tablet formulation resulted in rapid gastric dissolution and supersaturation, inducing adequate intestinal supersaturation and permeation of compound X, irrespective of the gastric acidity level in the stomach. In conclusion, this study describes the holistic biopharmaceutics approach driving the development of a patient-centric formulation of compound X.

Study on enteral nutrient components causing decreased gastric phenytoin absorption.

Previously, we revealed that coadministration of particular enteral nutrients (ENs) decreases plasma concentrations and gastric absorption of phenytoin (PHT), an antiepileptic drug, in rats; however, the mechanism has not been clarified. We measured the permeability rate of PHT using a Caco-2 cell monolayer as a human intestinal absorption model with casein, soy protein, simulated gastrointestinal digested casein protein (G-casein or P-casein) or simulated gastrointestinal digested soy protein (G-soy or P-soy), dextrin, sucrose, degraded guar gum, indigestible dextrin, calcium, and magnesium, which are abundant in the ENs, and measured the solution's properties. We demonstrated that casein (40 mg/ml), G-soy or P-soy (10 mg/ml), and dextrin (100 mg/ml) significantly decreased the permeability rate of PHT compared with the control. By contrast, G-casein or P-casein significantly increased the permeability rate of PHT. We also found that the PHT binding rate to casein 40 mg/ml was 90%. Furthermore, casein 40 mg/ml and dextrin 100 mg/ml have high viscosity. Moreover, G-casein and P-casein significantly decreased the transepithelial electrical resistance of Caco-2 cell monolayers compared with casein and the control. Casein, digested soy protein, and dextrin decreased the gastric absorption of PHT. However, digested casein decreased PHT absorption by reducing the strength of tight junctions. The composition of ENs may affect the absorption of PHT differently, and these findings would aid in the selection of ENs for orally administered PHT.

A Dynamic In Vitro Model for Testing Intestinal Absorption of Different Vegetable Food Secondary Metabolites

Cell-based bioreactors are important tools for evaluating molecule absorption in dynamic conditions, simulating simil-physiological flow, transport, and biological barriers. They allow for absorption and metabolization studies to be performed, obtaining very predictive data of in vivo conditions. In this paper, a new dynamic model is proposed to evaluate the intestinal absorption and toxicity of different vegetable food secondary metabolites, by using a LiveFlow® bioreactor. Different food secondary metabolites, such as caffeic, quinic, and rosmarinic acids, quercetin, and rutin, belonging to the polyphenols class, were selected. The aim was to study their different intestinal absorptions in order to validate this new system as an alternative strategy or a more advanced method compared to conventional culture systems for absorption screening and testing. The molecule absorption and the potential generation of metabolites were evaluated by RP-HPLC-DAD. This new dynamic platform represents a promising in vitro methodology which can provide more information than the traditional static in vitro approaches, and an efficient alternative to animal models, at least in preliminary experiments.

New understanding from intestinal absorption model: How physiological features influence mass transfer and absorption

AbstractMathematical modeling of mass transfer and absorption in the small intestine has been a challenging task. Systematic review and analysis of existing efforts indicate the need to pursue a reliable predictive model that is physically sound and computationally efficient. With the consideration of 3D intestinal inner wall structure, this work rigorously derives an absorption model that can be used as a source term in a 1D distributed model, conventionally called the diffusion–convection–reaction model. Moreover, computational fluid dynamics simulations are carried out to generate in silico experimental data for quantification of the mass‐transfer coefficient in the absorption model. This model facilitates a better understanding of the intricate influence of intestinal morphology and motility on mass transfer and absorption in the intestine. Rat duodenum featuring a villous structure and pendular movement is selected as an example to demonstrate the capability of this approach.

The Dynamic Intestinal Absorption Model (Diamod®), an in vitro tool to study the interconnected kinetics of gastrointestinal solubility, supersaturation, precipitation, and intestinal permeation processes of oral drugs

This study aimed at developing the Diamod® as a dynamic gastrointestinal transfer model with physically interconnected permeation. The Diamod® was validated by studying the impact of the intraluminal dilution of a cyclodextrin-based itraconazole solution and the negative food effect for indinavir sulfate for which clinical data are available demonstrating that the systemic exposure was strongly mediated by interconnected solubility, precipitation, and permeation processes. The Diamod® accurately simulated the impact of water intake on the gastrointestinal behavior of a Sporanox® solution. Water intake significantly decreased the duodenal solute concentrations of itraconazole as compared to no intake of water. Despite this duodenal behavior the amount of permeated itraconazole was not affected by water intake as observed in vivo. Next to this, the Diamod® accurately simulated the negative food effect for indinavir sulfate. Different fasted and fed state experiments demonstrated that this negative food effect was mediated by an increased stomach pH, entrapment of indinavir in colloidal structures and the slower gastric emptying of indinavir under fed state conditions. Therefore, it can be concluded that the Diamod® is a useful in vitro model to mechanistically study the gastrointestinal performance of drugs.

An ex vivo intestinal absorption model is more effective than an in vitro cell model to characterise absorption of dietary carotenoids following simulated gastrointestinal digestion

To get the most accurate food digestion-related data, and how this affects nutrient absorption, it is critical to carefully simulate human digestion systems using model settings. In this study, the uptake and transepithelial transportation of dietary carotenoids was compared using two different models that have previously been used to assess nutrient availability. The permeability of differentiated Caco-2 cells and murine intestinal tissue were tested using all-trans-β-carotene and lutein prepared in artificial mixed micelles and micellar fraction from orange-fleshed sweet potato (OFSP) gastrointestinal digestion. Transepithelial transport and absorption efficiency were then determined using liquid chromatography tandem-mass spectrometry (LCMS-MS). Results showed that the mean uptake for all-trans-β-carotene in the mouse mucosal tissue was 60.2 ± 3.2% compared to 36.7 ± 2.6% in the Caco-2 cells with the mixed micelles as the test sample. Similarly, the mean uptake was higher in OFSP with 49.4 ± 4.1% following mouse tissue uptake compared to 28.9 ± 4.3% using Caco-2 cells for the same concentration. In relation to the uptake efficiency, the mean percentage uptake for all-trans-β-carotene from artificial mixed micelles was 1.8-fold greater in mouse tissue compared to Caco-2 cells (35.4 ± 1.8% against 19.9 ± 2.6%). Carotenoid uptake reached saturation at 5 µM when assessed with the mouse intestinal cells. These results demonstrate the practicality of employing physiologically relevant models simulating human intestinal absorption processes that compares well with published human in vivo data. When used in combination with the Infogest digestion model, the Ussing chamber model, using murine intestinal tissue, may thus be an efficient predictor of carotenoid bioavailability in simulating human postprandial absorption ex vivo.

Selective isoxazolopyrimidine PAT1 (SLC26A6) inhibitors for therapy of intestinal disorders.

A loss of prosecretory Cl- channel CFTR activity in the intestine is considered as the key cause of gastrointestinal problems in cystic fibrosis (CF): meconium ileus, distal intestinal obstruction syndrome (DIOS) and constipation. Since CFTR modulators have minimal effects on gastrointestinal symptoms, there is an unmet need for novel treatments for CF-associated gastrointestinal disorders. Meconium ileus and DIOS mainly affect the ileum (distal small intestine). SLC26A6 (putative anion transporter 1, PAT1) is a Cl-/HCO3- exchanger at the luminal membrane of small intestinal epithelial cells which facilitates Cl- and fluid absorption. We recently identified first-in-class PAT1 inhibitors by high-throughput screening. Isoxazolopyrimidine PAT1inh-A01 was a hit compound, which had low potency (IC50 5.2 μM) for SLC26A6 inhibition precluding further preclinical development. Here we performed structure-activity relationship studies to optimize isoxazolopyrimidine SLC26A6 inhibitors and tested a potent inhibitor in mouse models of intestinal fluid absorption. Structure-activity studies of 377 isoxazolopyrimidine analogs identified PAT1inh-A0030 (ethyl 4-(benzyl(methyl)amino)-3-methylisoxazolo[5,4-d]pyrimidine-6-carboxylate) as the most potent SLC26A6 inhibitor with a 1.0 μM IC50. Selectivity studies showed that PAT1inh-A030 has no activity on relevant ion transporters/channels (SLC26A3, SLC26A4, SLC26A9, CFTR, TMEM16A). In a closed-loop model of intestinal fluid absorption, intraluminal PAT1inh-A0030 treatment inhibited fluid absorption in the ileum of wild-type and CF mice (CftrdelF508/delF508) with >90% prevention of a decrease in loop fluid volume and loop weight/length ratio at 30 minutes. These results suggest that SLC26A6 is the key transporter mediating Cl- and fluid absorption in the ileum and SLC26A6 inhibitors are novel drug candidates for treatment of CF-associated small intestinal disorders.

Critical features of an in vitro intestinal absorption model to study the first key aspects underlying food allergen sensitization.

New types of protein sources will enter our diet in a near future, reinforcing the need for a straightforward in vitro (cell-based) screening model to test and predict the safety of these novel proteins, in particular their potential risk for de novo allergic sensitization. The Adverse Outcome Pathway (AOP) for allergen sensitization describes the current knowledge of key events underlying the complex cellular interactions that proceed allergic food sensitization. Currently, there is no consensus on the in vitro model to study the intestinal translocation of proteins as well as the epithelial activation, which comprise the first molecular initiation events (ME1-3) and the first key event of the AOP, respectively. As members of INFOGEST, we have highlighted several critical features that should be considered for any proposed in vitro model to study epithelial protein transport in the context of allergic sensitization. In addition, we defined which intestinal cell types are indispensable in a consensus model of the first steps of the AOP, and which cell types are optional or desired when there is the possibility to create a more complex cell model. A model of these first key aspects of the AOP can be used to study the gut epithelial translocation behavior of known hypo- and hyperallergens, juxtaposed to the transport behavior of novel proteins as a first screen for risk management of dietary proteins. Indeed, this disquisition forms a basis for the development of a future consensus model of the allergic sensitization cascade, comprising also the other key events (KE2-5).

Acute High Dietary Phosphorus Following Low-Phosphorus Diet Acclimation Does Not Enhance Intestinal Fractional Phosphorus Absorption in Nephrectomized Male Rats.

Dietary phosphorus restriction and phosphorus binders are commonly prescribed for patients with chronic kidney disease (CKD). However, occurrences of non-adherence to these interventions are common. As low-phosphorus (LP) diets have been consistently experimentally shown in vitro to increase intestinal phosphorus absorption efficiency, a bout of non-adherence to diet or binders may cause an unintended consequence of enhanced intestinal phosphorus absorption. Thus, we aimed to determine the effect of a single bout of high-phosphorus (HP) intake after acclimation to a LP diet. Male Sprague Dawley rats with 5/6 nephrectomy (n=36) or sham operation (n=36) were block-randomized to 1 of 3 diets: LP (0.1% P w/w), HP (1.2%), or LP followed by acute HP (LPHP 0.1% then 1.2%). Phosphorus absorption tests were conducted using 33P radioisotope administrated by oral gavage or intravenously (iv). Although the overall two-way ANCOVA model for intestinal fractional phosphorus absorption was non-significant, exploratory comparisons showed intestinal fractional phosphorus absorption efficiency tended to be higher in rats in the LP compared with HP or LPHP groups. Rats in the HP or LPHP groups had higher plasma phosphorus compared with rats in the LP group, but the LPHP group was not different from the HP group. Gene expression of the major intestinal phosphate transporter, NaPi-2b, was lower in the jejunum of rats in the LPHP group compared with rats in the HP group but not different in the duodenum. These results demonstrate that an acute HP load after acclimation to a LP diet does not lead to enhanced intestinal fractional phosphorus absorption efficiency in 5/6 nephrectomized male rats. These data provide evidence against the notion that dietary phosphorus restriction or binder use adversely increases absorption efficiency after a single instance of dietary or binder non-adherence. However, other adverse consequences of fluctuating dietary phosphorus intake cannot be ruled out. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Menthol augmented niosomes for enhanced intestinal absorption of lopinavir

Lopinavir is effective in treatment of HIV infection but experiences low oral bioavailability due to poor solubility, pre-systemic metabolism, and P-gp intestinal efflux. Co-processing with menthol enhanced its dissolution and intestinal permeability. Niosomes comprising Span 60, cholesterol, and poloxamer 407 were formulated in absence and presence of menthol. These were evaluated for size, morphology, entrapment efficiency (EE%), lopinavir release, and intestinal absorption. The later employed in situ rabbit intestinal absorption model. Niosomes were spherical with vesicle size of 140.2 ± 23 and 148.2 ± 27 nm for standard and menthol containing niosomes, respectively. The EE% values were 94.4% and 96.3% for both formulations, respectively. Niosomes underwent slow release during the time course of absorption with menthol hastening lopinavir release, but the release did not exceed 9%. Niosmoal encapsulation enhanced lopinavir intestinal absorption compared with drug solution. This was reflected from the fraction absorbed from duodenum, which was 24.15%, 73.09%, and 83.23% for solution, standard niosomes and menthol containing vesicles, respectively. These values were 34.32%, 80.8%, and 86.56% for the same formulations in case of jejuno-ileum. Lopinavir absorption from niosomes did not depend on release supporting intact vesicle absorption. The study introduced menthol containing niosomes as carriers for enhanced lopinavir intestinal absorption.

Anti-Hyperglycemic Effects of Oils and Extracts Derived from Sea Buckthorn - A Comprehensive Analysis Utilizing In Vitro and In Vivo Models.

ScopeSea buckthorn (Hippophaes rhamnoides) is capable of ameliorating disturbed glucose metabolism in animal models and human subjects. Here, the effect of sea buckthorn oil as well as of extracts of fruits, leaves, and press cake on postprandial glucose metabolism is systematically investigated.Methods and resultsSea buckthorn did neither exert decisive effects in an in vitro model of intestinal glucose absorption nor did it alter insulin secretion. However, sea buckthorn stimulates GLUT4 translocation to the plasma membrane comparable to insulin, indicative of increased glucose clearance from the circulation. Isorhamnetin is identified in all sea buckthorn samples investigated and is biologically active in triggering GLUT4 cell surface localization. Consistently, sea buckthorn products lower circulating glucose by ≈10% in a chick embryo model. Moreover, sea buckthorn products fully revert hyperglycemia in the nematode Caenorhabditis elegans while they are ineffective in Drosophila melanogaster under euglycemic conditions.ConclusionThese data indicate that edible sea buckthorn products as well as by‐products are promising resources for hypoglycemic nutrient supplements that increase cellular glucose clearance into target tissues.

Application of Fucoidan in Caco-2 Model Establishment.

The Caco-2 model is a common cell model for material intestinal absorption in vitro, which usually takes 21 days to establish. Although some studies have shown that adding puromycin (PM) can shorten the model establishment period to 7 days, this still requires a long modeling time. Therefore, exploring a shorter modeling method can reduce the experimental costs and promote the development and application of the model. Fucoidan is an acidic polysaccharide with various biological activities. Our study showed that the transepithelial electrical resistance (TEER) value could reach 600 Ω·cm2 on the fourth day after the addition of fucoidan and puromycin, which met the applicable standards of the model (>500 Ω). Moreover, the alkaline phosphatase (AKP) activity, fluorescein sodium transmittance, and cell morphology of this model all met the requirements of model establishment. Fucoidan did not affect the absorption of macromolecular proteins and drugs. The results indicate that fucoidan can be applied to establish the Caco-2 model and can shorten the model establishment period to 5 days.

Predicting Impact of Food and Feeding Time on Oral Absorption of Drugs with a Novel Rat Continuous Intestinal Absorption Model.

Intricacies in intestinal physiology, drug properties, and food effects should be incorporated into models to predict complex oral drug absorption. A previously published human continuous intestinal absorption model based on the convection-diffusion equation was modified specifically for the male Sprague-Dawley rat in this report. Species-specific physiologic conditions along intestinal length - experimental velocity and pH under fasted and fed conditions, were measured and incorporated into the intestinal absorption model. Concentration-time (C-t) profiles were measured upon a single intravenous and peroral (PO) dose for three drugs: amlodipine (AML), digoxin (DIG), and glyburide (GLY). Absorption profiles were predicted and compared with experimentally collected data under three feeding conditions: 12-hour fasted rats were provided food at two specific times after oral drug dose (1 hour and 2 hours for AML and GLY; 0.5 hours and 1 hour for DIG), or they were provided food for the entire study. Intravenous versus PO C-t profiles suggested absorption even at later times and informed design of appropriate mathematical input functions based on experimental feeding times. With this model, AML, DIG, and GLY oral C-t profiles for all feeding groups were generally well predicted, with exposure overlap coefficients in the range of 0.80-0.97. Efflux transport for DIG and uptake and efflux transport for GLY were included, modeling uptake transporter inhibition in the presence of food. Results indicate that the continuous intestinal rat model incorporates complex physiologic processes and feeding times relative to drug dose into a simple framework to provide accurate prediction of oral absorption. SIGNIFICANCE STATEMENT: A novel rat continuous intestinal model predicts drug absorption with respect to time and intestinal length. Feeding time relative to dose was modeled as a key effect. Experimental fasted/fed intestinal pH and velocity, efflux and uptake transporter expression along intestinal length, and uptake transporter inhibition in the presence of food were modeled. The model uses the pharmacokinetic profiles of three model drugs and provides a novel framework to study food effects on absorption.

In vitro Bioaccessibility and Intestinal Absorption of Selected Bioactive Compounds in Terminalia ferdinandiana.

Terminalia ferdinandiana (or Kakadu plum), a native Australian fruit with potential health benefits, contains bioactive compounds such as ellagic acid (EA), ascorbic acid (AA) and calcium, and antinutrients such as oxalic acid (OA). However, few is known about the biological fate of these compounds following ingestion; therefore, the aim of this study was to evaluate in vitro bioaccessibility and intestinal absorption of T. ferdinandiana compounds using the INFOGEST static digestion model and Caco-2-HT29-MTX-E12 intestinal absorption model. No significant changes (p > 0.05) were observed in total AA content throughout in vitro digestion, whereas bioaccessibility of EA, OA, and calcium increased significantly from 33, 72, and 67% in the gastric phase to 48, 98, and 90% in the intestinal phase, respectively. The intestinal absorption study revealed variable rates of movement across the cell barrier. Findings reveal novel and important insights for the prediction of in vivo bioavailability of selected T. ferdinandiana compounds.

Preliminary screening of the potential active ingredients in traditional Chinese medicines using the Ussing chamber model combined with HPLC-PDA-MS

An in vitro intestinal absorption model combined with high-performance liquid chromatography-photo diode array-tandem mass spectrometry (HPLC-PDA-MS) was used for preliminary screening of potential active ingredients from complex multi-component traditional Chinese medicine (TCM) system. Oral administration is one of the main administration methods for TCMs. Only the ingredients that could be absorbed have the opportunity to play a role. Thus, these were defined as potential active ingredients. Studying of intestinal absorption can provide a theoretical basis for the mechanism of TCMs. The Caco-2 cell model, the everted rat gut sac model, and the Ussing chamber model were established for TCMs. The degree of anastomosis between the in vitro intestinal model and the actual intestinal absorption of TCMs were evaluated by the gavage method in rats. The Ussing chamber model was best fit for oral experiments in rats and was selected as the research means to preliminarily screen potential active ingredients from eight TCMs, including Salvia miltiorrhiza Bunge, Astragalus propinquus Schischkin, Plantago asiatica L, Fallopia multiflora (Thunb.) Harald, Epimedium brevicornu Maxim, Moutan Cortex, Citrus reticulata Blanco, and Panax notoginseng (Burkill) F. H. Chen ex C. H. Chow. A total of 44 components were absorbed and screened as the potential active ingredients from the 80 components identified in eight TCMs by HPLC-PDA-MS.