Study on enteral nutrient components causing decreased gastric phenytoin absorption.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Preparation of nanoliposomes loaded with anthocyanins from grape skin extracts: stability, gastric absorption and antiproliferative properties.

Anthocyanin nanoliposomes (ANLs) were produced by a thin film ultrasonic dispersion method to improve the stability and bioavailability of anthocyanins (ACNs) obtained from grape skin extracts. The preparation parameters were predicted to be a soy lecithin to cholesterol ratio of 80 : 19 (w/w, 2 mg of ACNs) under ultrasonication at 120 W for 3.12 min by the response surface methodology. Under the optimal conditions, the fabricated ANLs presented an encapsulation efficiency of 40.1% with an average particle size of 117 nm, a PDI of 0.254 and a ζ-potential of 8.56 mV. The stability of ACNs was improved by nanoliposome encapsulation under various temperature and light conditions. Moreover, a MKN-28 (stomach) barrier model was established to evaluate the cellular transport of ACNs before and after nanoliposome encapsulation. HPLC-DAD/MS analyses demonstrated that ACNs obtained from grape skin extracts mainly consisted of five monomers. After 180 min of transportation, peonidin-3-5-diglucoside and malvidin-3-5-diglucoside (two representative monomers) present in ANLs (0.5 mg mL-1) showed the maximum transport efficiencies of 17.25 ± 1.62% and 18.94 ± 1.05%, respectively. However, their maximum transport efficiencies were 11.68 ± 1.01% and 15.33 ± 1.24%, respectively, existing in ACNs (non-encapsulated form, 0.5 mg mL-1). Furthermore, the antiproliferative properties of ANLs were assessed in two cancer cell lines MKN-28 and HepG-2 (liver). The ANLs presented more effective antiproliferative effects towards MKN-28 than the HepG-2 cell line. This study provides theories and a practice foundation for further application of ACNs as nutraceutical and functional foods.

Microencapsulation of Ionic Liquid by Interfacial Self-Assembly of Metal-Phenolic Network for Efficient Gastric Absorption of Oral Drug Delivery.

Improving bioavailability of orally delivered drugs is still challenging, as conventional drug delivery systems suffer from non-specific drug delivery in the gastrointestinal (GI) tract and limited drug absorption efficiency. Gastric drug delivery is even more difficult due to the harsh microenvironment, short retention time, and physiologic barriers in the stomach. Here, an oral drug delivery microcapsule system was developed for gastric drug delivery, which consists of ionic liquid (IL) as the inner carrier and metal-phenolic network (MPN) as the microcapsule shell. The IL@MPN microcapsules are prepared by interfacial self-assembly of FeIII and quercetin at the interface of hydrophobic IL ([EMIM][NTf2]) and water. The formation of MPN shell could improve the stability of IL droplets in water and endow the system with pH-response drug release properties, while the encapsulated IL core could efficiently load the drug and enhance the drug tissue permeability. The IL@MPN microcapsules showed enhanced drug absorption in the stomach after oral administration in a rat model, where the microcapsules are disassembled in gastric acid, and the released IL could reduce the viscosity of mucus gel and increase the drug transport rate across endothelial cells. This work presents a simple yet efficient strategy for oral drug delivery to the stomach. Given the diversity and versatility of both MPN and IL, the proposed self-assembled microcapsules could expand the toolbox of drug delivery systems with enhanced oral drug bioavailability.

Direct Acting Oral Anticoagulants Following Gastrointestinal Tract Surgery.

ABSTRACT: Direct-acting oral anticoagulants (DOACs) vary in bioavailability and sites of absorption in the gastrointestinal tract (GIT). Data on DOAC use after major GIT surgery are limited. The aim of this case series was to report the impact of surgical resection or bypass of the GIT on rivaroxaban and apixaban peak plasma concentrations. This was a case series of patients who received rivaroxaban or apixaban after GIT surgery, during the period of July 1, 2019, to December 31, 2020. Peak plasma concentrations of rivaroxaban and apixaban were assessed for the expected concentrations. Of the 27 assessed patients, 18 (66.7%) received rivaroxaban, and 9 (33.3%) received apixaban. After rivaroxaban therapy, 4 of 5 patients (80%) who underwent gastrectomy, and 3 of 3 patients (100%) who underwent duodenum and proximal jejunum exclusion had peak plasma concentrations of rivaroxaban lower than the effective range, whereas 11 of 11 patients (100%) who underwent distal bowel or ileostomy had peak rivaroxaban plasma within the effective range. After apixaban therapy, 5 of 6 patients (83.3%) who underwent total or partial gastrectomy achieved effective peak concentrations. All the patients who underwent proximal and distal bowel resection or bypass had peak concentrations of apixaban within the effective range. In conclusion, surgical resection or bypass of the upper GIT could affect DOAC absorption and subsequently peak plasma concentrations. This effect was more observed among rivaroxaban recipients. An injectable anticoagulant or vitamin K antagonist may be preferred if DOAC concentrations cannot be measured after GIT surgery.

SIDT1-dependent absorption in the stomach mediates host uptake of dietary and orally administered microRNAs.

Dietary microRNAs have been shown to be absorbed by mammals and regulate host gene expression, but the absorption mechanism remains unknown. Here, we show that SIDT1 expressed on gastric pit cells in the stomach is required for the absorption of dietary microRNAs. SIDT1-deficient mice show reduced basal levels and impaired dynamic absorption of dietary microRNAs. Notably, we identified the stomach as the primary site for dietary microRNA absorption, which is dramatically attenuated in the stomachs of SIDT1-deficient mice. Mechanistic analyses revealed that the uptake of exogenous microRNAs by gastric pit cells is SIDT1 and low-pH dependent. Furthermore, oral administration of plant-derived miR2911 retards liver fibrosis, and this protective effect was abolished in SIDT1-deficient mice. Our findings reveal a major mechanism underlying the absorption of dietary microRNAs, uncover an unexpected role of the stomach and shed light on developing small RNA therapeutics by oral delivery.

Enhancing delayed release characteristics of chapparada avare seed starch.

This study aims to evaluate the effects of pregelatinization in improving delayed release characteristics of native chapparada avare starch. Physicochemical properties and drug release characteristics were evaluated for the native and pregelatinized starches using established methods. The moisture content decreased from 12.13 ± 0.15% to 8.73 ± 0.12%, whereas amylose content (6.91 ± 0.06-21.13 ± 0.03), swelling power and water holding capacity (211.04 ± 0.03-513.03 ± 0.03) showed steady rise with pregelatinization time. The result of X ray diffraction pattern for pregelatinized starch, showed absence of 18.4° and 23.2° 2θ peaks thereby indicating reducing crystallinity, compared to native starch, whereas FESEM micrograph showed complete disruption of granular structure due to pregelatinization of native starch. The in vitro dissolution studies conducted in gastric and intestinal pH showed that tablets prepared with both native (NPL) and modified starch (PG15, PG20, PG 25), are gastro protective with less than 25% drug release in pH 1.2. In pH 6.8, PG 20 and PG 25 showed optimum drug release of 21.23 ± 0.54% and 19.40 ± 0.48% respectively in 6 h compared to 42.52 ± 0.21% release of NPL formulation, thereby indicating time based delayed drug release characteristics of over its native counterpart.

Effect of Humic Acids from Lowland Peat on Endurance of Rats in Forced Swim Test in Relation to Serum Lactate and Corticosterone.

The study substantiated the possibility of using peat humic acids for improving endurance during extreme physical exertion. The mature outbred Wistar rats weighing 200-250 g (n=40) were subjected to forced swim test until complete exhaustion. The humic acids (1%) were administered intragastrically (0.5 ml/100 g body weight) 30 min prior to the test. Chronic administration of peat humic acids for 5 days increased physical capacity and endurance of rats in exhaustive forced swim test without the changes in serum lactate and corticosterone.

A revised Sorensen model: Simulating glycemic and insulinemic response to oral and intra-venous glucose load.

In 1978, Thomas J. Sorensen defended a thesis in chemical engineering at the University of California, Berkeley, where he proposed an extensive model of glucose-insulin control, model which was thereafter widely employed for virtual patient simulation. The original model, and even more so its subsequent implementations by other Authors, presented however a few imprecisions in reporting the correct model equations and parameter values. The goal of the present work is to revise the original Sorensen's model, to clearly summarize its defining equations, to supplement it with a missing gastrio-intestinal glucose absorption and to make an implementation of the revised model available on-line to the scientific community.

Oral delivery of protein-based therapeutics: Gastroprotective strategies, physiological barriers and in vitro permeability prediction.

The number of biological molecules emerging as therapeutics is growing exponentially due to their higher specificity and tolerability profiles compared to small molecules. Despite this, their traditionally parenteral delivery often results in poor patient compliance and incomplete treatment. Current research is focussed on developing effective oral delivery strategies to facilitate administration of these biomolecules, however no universal method exists to simultaneously provide gastric protection as well as enhance transport across the gastrointestinal epithelium. Furthermore, for efficient formulation development it is imperative that we can reliably analyse permeability of biomolecules through the gastrointestinal tract, highlighting the importance of the continual development and ongoing evaluation of in vitro predictive permeability tools. Here, we review the physiological obstacles associated with peptide and protein delivery throughout the gastrointestinal tract. Furthermore, we highlight methods utilised to circumvent these barriers and promote improved intestinal permeability. Lastly, we explore in vitro models employed to predict epithelial transport. Key findings highlight the need to carefully understand gastrointestinal physiology, allowing specific engineering of oral delivery systems for biomolecules. Significant importance is placed upon understanding enzymatic degradation susceptibility as well as uptake mechanisms for particulate and protein-based therapeutics for the development of successful oral protein delivery platforms.

Clinical implications of food-drug interactions with small-molecule kinase inhibitors.

During the past two decades, small-molecule kinase inhibitors have proven to be valuable in the treatment of solid and haematological tumours. However, because of their oral administration, the intrapatient and interpatient exposure to small-molecule kinase inhibitors (SMKIs) is highly variable and is affected by many factors, such as concomitant use of food and herbs. Food-drug interactions are capable of altering the systemic bioavailability and pharmacokinetics of these drugs. The most important mechanisms underlying food-drug interactions are gastrointestinal drug absorption and hepatic metabolism through cytochrome P450 isoenzymes. As food-drug interactions can lead to therapy failure or severe toxicity, knowledge of these interactions is essential. This Review provides a comprehensive overview of published studies involving food-drug interactions and herb-drug interactions for all registered SMKIs up to Oct 1, 2019. We critically discuss US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines concerning food-drug interactions and offer clear recommendations for their management in clinical practice.

Physiologically Based Absorption Modelling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Entrectinib.

Entrectinib is a potent and selective tyrosine kinase inhibitor (TKI) of TRKA/B/C, ROS1, and ALK with both systemic and CNS activities, which has recently received FDA approval for ROS1 fusion-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. This paper describes the application of a physiologically based biophamaceutics modeling (PBBM) during clinical development to understand the impact of food and gastric pH changes on absorption of this lipophilic, basic, molecule with reasonable permeability but strongly pH-dependent solubility. GastroPlus™ was used to develop a physiologically based pharmacokinetics (PBPK) model integrating in vitro and in silico data and dissolution studies and in silico modelling in DDDPlus™ were used to understand the role of self-buffering and acidulant on formulation performance. Models were verified by comparison of simulated pharmacokinetics for acidulant and non-acidulant containing formulations to clinical data from a food effect study and relative bioavailability studies with and without the gastric acid-reducing agent lansoprazole. A negligible food effect and minor pH-dependent drug-drug interaction for the market formulation were predicted based on biorelevant in vitro measurements, dissolution studies, and in silico modelling and were confirmed in clinical studies. These outcomes were explained as due to the acidulant counteracting entrectinib self-buffering and greatly reducing the effect of gastric pH changes. Finally, sensitivity analyses with the verified model were applied to support drug product quality. PBBM has great potential to streamline late-stage drug development and may have impact on regulatory questions.

The dynamic process of dietary soybean ß-conglycinin in digestion, absorption, and metabolism among different intestinal segments in grass carp (Ctenopharyngodon idella).

The present study aimed to investigate the dynamic process of soybean ß-conglycinin in digestion, absorption, and metabolism in the intestine of grass carp (Ctenopharyngodon idella). Fish fed with 80 g ß-conglycinin/kg diet for 7 weeks, the intestinal digestive enzyme was extracted to hydrolyze ß-conglycinin in vitro, the free amino acid and its metabolism product contents in intestinal segments were analyzed. The present study first found that ß-conglycinin cannot be thoroughly digested by fish intestine digestive enzyme and produces new products (about 60- and 55-kDa polypeptides). The indigestible ß-conglycinin further caused the free amino acid imbalance, especially caused free essential amino acid deficiency in the proximal intestine but excess in the distal intestine. Moreover, these results might be partly associated with the effect of ß-conglycinin in amino acid transporters and tight junction-regulated paracellular pathway. Finally, dietary ß-conglycinin increased the content of amino acid catabolism by-product ammonia while decreased the amino acid anabolism product carnosine content in the proximal intestine and distal intestine. Thus, the current study first and systemically explored the dynamic process of ß-conglycinin in digestion, absorption, and metabolism, which further supported our previous study that dietary ß-conglycinin suppressed fish growth and caused intestine injure.

Levothyroxine Therapy in Gastric Malabsorptive Disorders.

Oral levothyroxine sodium is absorbed in the small intestine, mainly in the jejunum and the ileum being lower the absorption rate at duodenal level. The time interval between the ingestion of oral thyroxine and its appearance in the plasma renders unlike a gastric absorption of the hormone. However, several evidence confirm the key role of the stomach as a prerequisite for an efficient absorption of oral levothyroxine. In the stomach, in fact, occur key steps leading to the dissolution of thyroxine from the solid form, the process bringing the active ingredient from the pharmaceutical preparation to the aqueous solution. In particular, gastric juice pH, volume, viscosity, as well as gastric emptying time seem to be the most important limiting factors. These hypotheses are confirmed by the detection of an increased need for levothyroxine in patients with Helicobacter pylori infection, chronic atrophic gastritis, gastroparesis, or in simultaneous treatment with drugs interfering with gastric acidic output. The aim of the present article is to focus on the knowledge of pathophysiologic events that determine the absorptive fate of traditional (tablet) and alternative thyroxine preparations (softgel capsule and liquid solution) in patients bearing gastric disorders.

Development of novel bilayer gastroretentive tablets based on hydrophobic polymers.

This study aimed to develop a bilayer gastroretentive (GR) tablet containing an insoluble drug and ascertain the potential of using hydrophobic polymers in GR matrix systems. Highly porous tablets were prepared using a camphor-based sublimation technique. After the screening of several commonly used polymers, two types of GR layers, a conventional hydrophilic GR layer and a hydrophobic GR layer, were designed. The optimal drug layer comprising Metolose® 90SH-100SR and dicalcium phosphate provided not only a gradual matrix erosion but also high strength after hydration. Regarding the GR layers, the hydrophobic layer based on Kollidon® SR was superior to the hydrophilic layer made of PEO 7 M in terms of wet strength, implying a higher resistance to mechanical stresses upon water absorption. Also, the excellent tableting properties of Kollidon® SR and the effects of curing in improving its matrix hardness resulted in porous tablets with better mechanical strength. Moreover, good flowability and low cohesion of Kollidon® SR formulation were advantageous in direct compression. In conclusion, novel bilayer GR tablets were successfully developed, indicating the potential for widening the application of GR systems to insoluble drugs. The results also suggested numerous advantages of incorporating Kollidon® SR into the production of GR tablets.

Swellable and porous bilayer tablet for gastroretentive drug delivery: Preparation and in vitro-in vivo evaluation.

The purpose of this study was to develop a novel gastroretentive drug delivery system with immediate buoyancy and high wet strength. The proposed bilayer tablet was composed of a drug layer and a highly porous and swellable gastroretentive (GR) layer. The highly porous GR layer was prepared by sublimating the volatile materials after compaction with swellable polymers. This pore-forming process decreased the density of the GR layer and enabled the tablet to float immediately on the dissolution media. The GR layer formulation was optimized by comparing the swelling, erosion, and mechanical properties of candidate swellable polymers. The release rates were conveniently controlled by changing the polymer content in the drug layer, while the swelling and floating properties were provided by the GR layer. The application of percolation theory revealed that the polymer content above the estimated threshold was required for a reliable drug release profile. In vivo study in fed beagle dogs confirmed the enhanced gastric retention time of the tablets compared to that of conventional single layer tablets. Taken together, our data suggest that the proposed system can be a promising platform technology with superior GR properties and a convenient formulation process.

Food, Acid Supplementation and Drug Absorption - a Complicated Gastric Mix: a Randomized Control Trial.

PURPOSE: The purpose of this study was to determine the impact of food on gastric pH and the ability of over the counter betaine hydrochloride (BHCl) acid to reacidify gastric pH after food-induced elevations in gastric pH. METHODS: This open-label cross over clinical study (NCT02758015) included 9 subjects who were randomly assigned to one of 16 possible, 4-period cross-over sequences to determine the impact and relationship of food and gastric pH with acid supplementation. Subjects were administered various doses (1500 mg, 3000 mg and 4500 mg) of betaine hydrochloride (BHCl) to determine the ability of acid supplementation to reacidify gastric pH after the elevation of gastric pH caused by the ingestion of food. RESULTS: Following the administration of food and the resulting elevation in gastric pH, time to return to baseline gastric pH levels without acid supplementation was 49.7 ± 14.0 min. Administering 4500 mg of BHCl acid in capsules was able to reacidify gastric pH levels back to baseline following the administration of food in approximately 17.3 ± 5.9 min. AUCpH of each treatment were similar and not statistically different. Mean max pH following the administration of food was 3.20 ± 0.55. CONCLUSION: The ability of food to elevate and maintain gastric pH levels in the presence of acid supplementation was made evident throughout the study. A 4500 mg dose of BHCl was required to reacidify gastric pH after the administration of food. This study details the difficulty faced by clinicians in dosing a poorly soluble, weakly basic drug to patients receiving acid reducing agents where administration with food is recommended to avoid gastric side effects. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02758015.

A randomized, crossover study of the acute effects of acarbose and gastric distension, alone and combined, on postprandial blood pressure in healthy older adults.

BACKGROUND: Postprandial hypotension (PPH) occurs frequently in the elderly and patients with type 2 diabetes, and lacks a satisfactory treatment. Gastric distension and the α-glucosidase inhibitor, acarbose, may attenuate the postprandial fall in blood pressure (BP) by complementary mechanisms. We aimed to determine whether gastric distension and acarbose have additive effects to attenuate the fall in BP induced by oral sucrose. METHODS: Ten healthy older adults (74.0 ± 1.4 yr) had measurements of BP and superior mesenteric artery (SMA) blood flow for 120 min after receiving either (i) the 'study drink' of 100 g sucrose in 300 mL of water (control treatment), (ii) a 300 mL water 'preload' 15 min before the 'study drink' (distension treatment), (iii) 100 mg acarbose dissolved in the 'study drink' (acarbose treatment) or (iv) a 300 ml water 'preload' 15 min before 100 mg acarbose dissolved in the 'study drink' (acarbose and distension treatment). RESULTS: The area under the curve (AUC)0-120min for mean arterial pressure (MAP) was greater (P = 0.005) and the maximum fall in MAP was less (P = 0.006) during treatments with acarbose. Gastric distension did not affect the MAP-AUC0-120min response to acarbose (P = 0.44) and there was no effect of gastric distension alone (P = 0.68). Both acarbose treatments attenuated the rise in SMA blood flow (P = 0.003), whereas gastric distension had no effect. CONCLUSIONS: In healthy older adults, acarbose (100 mg), but not gastric distension, attenuates the fall in BP and rise in SMA blood flow after oral sucrose. The observations support the use of acarbose, but not gastric distension, to attenuate a postprandial fall in BP. TRIAL REGISTRATION: The study was retrospectively registered at ( ACTRN12618000152224 ) on February 02nd 2018.

Effects of Bariatric Surgery Observed in Postmortem Toxicology Casework.

Bariatric surgery has been on the rise and patients often have multiple indications for pre- and post-operative pharmacotherapy. Procedures target the stomach and/or small intestine and affect weight loss through restriction, malabsorption, or a combination of the two. The absorption and/or metabolism of drugs via the gastrointestinal tract could be altered by different mechanisms. Several cases at the North Carolina Office of the Chief Medical Examiner's Toxicology Laboratory (NCOCME) have raised questions about the potential impact of these procedures on the disposition of drugs in the body and how that altered disposition may affect cause and manner of death. Overmedication and postmortem redistribution are not enough to explain the phenomena seen in some NCOCME bariatric surgery-related casework. Case examples include a 46-year-old female with a history of Roux-en-Y gastric bypass (RYGB) who suffered a witnessed collapse. Toxicological findings included elevated concentrations of oxymorphone at 0.49 mg/L in vena cava blood. A 67-year-old female, who died from vomiting and bacterial gastritis one day after placement of two intragastric weight-loss balloons, had elevated concentrations of duloxetine at 1.4 mg/L in the iliac vein blood and 9.3 mg/kg in the liver. Her medication was strictly controlled by her sister and gastric contents were without intact tablets or residue at autopsy.

Metabolism of lysergic acid diethylamide (LSD): an update.

Lysergic acid diethylamide (LSD) is the most potent hallucinogen known and its pharmacological effect results from stimulation of central serotonin receptors (5-HT2). Since LSD is seen as physiologically safe compound with low toxicity, its use in therapeutics has been renewed during the last few years. This review aims to discuss LSD metabolism, by presenting all metabolites as well as clinical and toxicological relevance. LSD is rapidly and extensively metabolized into inactive metabolites; whose detection window is higher than parent compound. The metabolite 2-oxo-3-hydroxy LSD is the major human metabolite, which detection and quantification is important for clinical and forensic toxicology. Indeed, information about LSD pharmacokinetics in humans is limited and for this reason, more research studies are needed.