Oral Absorption Research Articles

Patients with heart failure with reduced ejection fraction are at high risk for iron deficiency (ID) due to low intake and high losses. Randomized controlled trials show intravenous (IV) iron improves quality of life and lowers readmissions. Suboptimal ID screening may stem from limited awareness of ID thresholds and guidelines in heart failure. We hypothesized that implementing provider education and optimized EHR notification would improve ID screening and IV iron infusion rates over 6 months among inpatients at a community hospital. Presentations were delivered to the Internal Medicine Residents, Hospitalists, and Cardiologists, reviewing key trials and recommendations for ID in CHF from the European Society of Cardiology (ESC), the American College of Cardiology (ACC), and the American Heart Association (AHA). A flyer summarizing diagnostic criteria and IV iron treatment was then posted in high-traffic provider areas. A Best Practice Alert (BPA) was also implemented, which triggered if a patient had heart failure and no iron studies in the past 6 months, automatically adding iron study orders unless removed. IV iron was recommended through education via presentations and flyers, using criteria of ferritin <100 ng/mL or 100–299 ng/mL with TSAT <20%. Pre-intervention data (PRE) were collected from 10/1/2024 - 2/13/2025, and post-intervention (POST) from 2/14 - 5/20/2025. Exclusions included previous iron studies or iron supplementation within 6 months. A chi-square test of independence was performed to measure if there was a statistically significant difference between PRE and POST for ID screening, IV infusion, and oral iron rates. 2,461 encounters met inclusion criteria (PRE: 1,507, POST: 954). Prior to the intervention, 12.8% were screened for ID compared to 24.1% after intervention with an Absolute Benefit Increase of 11.3% (p < 0.001). The rate of IV iron repletion increased significantly (PRE: 4.8% vs. POST: 6.8%, p < 0.05). Oral iron repletion rates were not significantly different in PRE vs. POST (4.5% to 4.8%, p > 0.05). ID screening improved with minimal burden via provider education and BPAs. IV iron use rose modestly, limited by reliance on education alone and brief hospital stays with competing clinical priorities. Future efforts should target education on oral iron absorption limitations, investigate barriers to IV iron infusion, and optimize the outpatient transition for continued ID management.

Indazole partial agonists targeting peripheral cannabinoid receptors.

Applicability of kinetically-based maximum dose studies for hazard and risk assessments of the fungicide fluoxapiprolin.

Design, synthesis, and preclinical evaluation of novel 1-benzylpiperidine derivatives as multitarget agents against Alzheimer's disease.

Functional and morphological characterisation of human colonoid-derived monolayers under inflammatory conditions.

Analysis of discrepancy in SNEDDS performance for a "brick dust" mebendazole between in and vitro and in-vivo estimation.

The passive membrane permeation of small-molecule drugs and small hydrophobic peptides is relatively well understood. In contrast, how long polar peptides can pass through a membrane has remained a mystery. This process can be achieved with permeation enhancers, contributing significantly to the oral transcellular absorption of important peptide drugs like semaglutide — the active pharmaceutical ingredient in Ozempic, which is used as Rybelsus in a successful oral formulation. Here we now provide a detailed, plausible molecular mechanism of how such a polar peptide can realistically pass through a membrane paired with the permeation enhancer salcaprozate sodium (SNAC). We provide both simulation results, obtained with scalable continuous constant pH molecular dynamics (CpHMD) simulations, and experimental evidence (NMR, DOSY, and DLS) to support this unique permeation mechanism. Our combined evidence points toward the formation of permeation-enhancer-filled, fluid membrane defects, in which the polar peptide can be submerged in a process analogous to quicksand.

This study provides insights into the in vivo performance of amorphous solid dispersion (ASD) formulations of a poorly water-soluble drug through deconvolution analysis using a surrogate marker for drug release. Carbamazepine (CAR) and fenofibrate (FEN) were used as surrogate markers of drug release from formulations and as a model of a poorly water-soluble drug, respectively. Three ASDs containing CAR (3 wt %) and FEN (30 wt %) were prepared using hydroxypropyl methylcellulose (HPMC) with immediate-release characteristics (ASD-HPMC) and two HPMC derivatives (HPMC acetate succinate, HPMCAS) exhibiting different pH-dependent drug release profiles (ASD-HPMCAS-LF and ASD-HPMCAS-HF). The in vitro drug release profiles of FEN for each ASD were comparable to those of CAR, with both compounds demonstrating polymer-dependent release behavior (release rate: ASD-HPMC > ASD-HPMCAS-LF > ASD-HPMCAS-HF). Slower FEN release prolonged the time to reach the maximum concentration; however, the maximum concentration itself was not affected. The improved oral FEN absorption in rats ranked as follows: ASD-HPMC > ASD-HPMCAS-HF > ASD-HPMCAS-LF, while CAR was completely absorbed regardless of the polymer used. Plasma CAR profile deconvolution analysis revealed that the in vivo drug release profiles corresponded to the in vitro release results. In the FEN absorption rate time-profiles, a hybrid parameter combining the drug concentration and absorption clearance, derived from deconvolution analysis, showed that ASD-HPMC maintained a relatively high and stable absorption rate until complete absorption. Conversely, ASD-HPMCAS-LF exhibited a half absorption rate compared to ASD-HPMC over 1.5 h, which then declined rapidly, resulting in limited FEN absorption improvement. For ASD-HPMCAS-HF, the absorption rate gradually increased and remained at half the rate compared to ASD-HPMC over 6 h, leading to an intermediate improvement in FEN absorption in three ASDs. These differences in absorption rate profiles indicate that drug release profiles significantly affect the amount of dissolved FEN, its retention time in the gastrointestinal tract, and the effective surface area available for absorption. This study demonstrates that the proposed method enables reliable evaluation of the in vivo performance of ASD formulations.

Abstract Depression prevalence is significantly higher (20‐40%) in inflammatory bowel disease (IBD) patients than the general population. Dysregulation of the gut microbiota‐brain axis (GM‐BA) is implicated in IBD‐associated depression pathogenesis, involving M1 macrophage‐driven neuroinflammation. While glycyrrhizic acid (GA) possesses anti‐inflammatory and neuroprotective properties, its poor oral absorption limits clinical use. To overcome this, we developed an innovative oral delivery system, IN@MOTOR@GA (IMG). It consists of Janus nanomotors encapsulated within an inulin hydrogel. The hydrogel protects the nanomotors in the stomach and enables targeted colonic release. At inflamed sites, the nanomotors utilize overexpressed H 2 O 2 to generate oxygen propelling autonomous motion, enhancing drug penetration and alleviating hypoxia. Metabolized inulin acts as a prebiotic, promoting probiotic growth and restoring gut microecology. In vivo studies demonstrated that IMG significantly alleviated murine colitis, restoring mucosal integrity and reducing pro‐inflammatory cytokines. Critically, IMG mitigated hippocampal neuroinflammation by modulating peripheral immunity and promoting a neuroprotective microglial phenotype, ultimately improving depressive‐like behaviors. This study introduces a groundbreaking GM‐BA‐targeted therapy offering a novel strategy for synergistic IBD and psychiatric comorbidity management.

Binary lipid system-based granules with undissolved drug crystals enhance oral bioavailability by preventing degradation and improving permeability.

Abstract Disclosure: G. Arora: None. V. Perugu: None. A.T. Drincic: None. Introduction: AVP-D is an endocrine disorder characterized by non-osmotic polyuria, treated with Desmopressin (DDAVP), an AVP analog. Drug resources indicate that food may reduce absorption of oral DDAVP. However, reportedly it does not affect its pharmacodynamics; as such, no precautions are currently advised with food intake or tube feeds. Here, we present two cases where severe polyuria and hypernatremia developed after tube feeds were initiated in patients receiving oral DDAVP, which corrected upon switch to subcutaneous (sq) DDAVP. Case Presentation: Case 1: A 65-year-old female with craniopharyngioma s/p resection and AVP-D on oral DDAVP presented to the emergency department for altered mentation and possible stroke. Na on admission was 141 mmol/L. Subsequently, tube feeds were initiated; and within a day of tube feeds initiation, she developed severe hypernatremia (Na 176 mmol/L, increased from Na 141 mmol/L the day prior) with polyuria, urine output increased to 1.6 ml/kg/hr from 0.5-1 ml/kg/hr on days prior (normal range: 0.5 - 1.5 ml/kg/hr). Oral DDAVP was discontinued and sq DDAVP was initiated with normalization of Na. She remained on tube feeds and was discharged on sq DDAVP, and Na remained normal for weeks with concentrated urine. Case 2: A 19-year-old female with panhypopituitarism and AVP-D on oral DDAVP and G-tube dependence on bolus tube feeds was admitted for hypernatremia - Na 175 mmol/L. Her mother had noted increased urinary output. Medical records indicated that DDAVP was being given with tube feeds. DDAVP was switched to sq. Water balance was restored and Na improved to 141 mmol/L. She was discharged on sq DDAVP, and Na remained normal over the next few months with control of polyuria. Conclusion: We report two cases of non-osmotic polyuria with hypernatremia in patients with AVP-D who received oral DDAVP with tube feeds. We postulate that concurrent administration of tube feeds caused DDAVP malabsorption. The only study evaluating oral DDAVP absorption has shown a 40% reduction when DDAVP is ingested within 90 minutes of a standard meal; however, no effect on pharmacodynamics has been reported. No studies have evaluated oral DDAVP absorption in relation to tube feeds. This becomes even more important in this vulnerable population of patients receiving tube feeds because a majority of them have a concomitantly decreased sense of thirst preventing intake of free water to restore Na-water balance. This warrants further investigation of this phenomenon; and if it holds true, then inclusion of a warning on UptoDate, Micromedex and Lexicom. Until further studies are done, we recommend switching to sq DDAVP dosing in hospitalized patients on tube feeds (especially those with adipsia). Alternative solutions such as increasing oral DDAVP dose and separating oral DDAVP from tube feeds in time - as with Levothyroxine - would need to be studied. Presentation: Monday, July 14, 2025

Coronary artery disease (CAD) is still a primary cause of death worldwide, prompting the development of innovative therapeutic strategies. In this work, 149 possible candidates were identified by creating a ligand-based pharmacophore model of traditional Chinese herbal medicines using FDA-approved CAD drugs as templates. Licoisoflavanone (MOL004885) was identified as the most promising dual inhibitor by subsequent molecular docking against the chemokine receptors CXCR4 and CXCR7. It showed significant binding affinities of −10.1 kcal/mol and −9.5 kcal/mol, respectively. Licoisoflavanone’s stability inside the binding sites of both receptors was validated by molecular dynamics simulations conducted over 200 ns, and MMGBSA analysis revealed a particularly advantageous interaction with CXCR4. Stereoisomeric analysis of the [Formula: see text]- and [Formula: see text]-forms of Licoisoflavanone revealed comparable stability and interaction patterns with both receptors. Pharmacokinetic predictions demonstrated nonmutagenic properties and good oral absorption. Additionally, the chemical stability and reactivity balance of the molecule were confirmed using density functional theory (DFT) calculations. These findings further support the dual-targeting potential of both enantiomers. All of these results point to Licoisoflavanone as a good candidate for additional research and development as a novel therapeutic drug that targets CXCR4/CXCR7 in the treatment of CAD.

Curcumin is a natural polyphenolic compound extracted from the rhizomes of Curcuma longa, exhibiting a wide range of biological activities, including anti-inflammatory, antioxidant, antitumor, antibacterial, antiviral, and neuroprotective effects. However, its low oral absorption rate and poor bioavailability limit its clinical application. To address this issue, this study synthesized a novel curcumin derivative, AN02, which significantly improves the absorption rate and bioavailability while enhancing its antitumor activity. This study focused on the antitumor mechanism of AN02 in ovarian cancer, particularly its ability to inhibit ovarian cancer cell proliferation, invasion, and migration by regulating the APC (Adenomatous Polyposis Coli)-SMAD4 (SMAD family member 4)-CTLA-4 (Cytotoxic T-Lymphocyte-Associated Protein 4) molecular axis. Experimental results demonstrated that AN02 significantly inhibited ovarian cancer cell proliferation at very low concentrations, with its half-maximal inhibitory concentration (IC50) significantly lower than that of curcumin. Additionally, AN02 exerted its antitumor effects by activating the APC-SMAD4 molecular axis and inhibiting the CTLA-4 molecular axis. Silencing CTLA-4 inhibits the proliferation and immune escape of ovarian cancer. Further molecular mechanism studies revealed that APC directly regulates the SMAD4-CTLA-4 molecular axis, while SMAD4 forms a chaperone relationship with CTLA-4 and promotes CTLA-4 degradation through the K48-dependent ubiquitination pathway, thereby suppressing the malignant phenotype of ovarian cancer cells. These findings not only reveal the antitumor mechanism of AN02 but also provide new insights for the treatment of ovarian cancer. Animal experiments also demonstrated that AN02 significantly inhibits the proliferation of subcutaneous xenograft tumors in mice. As a novel curcumin derivative, AN02 exhibits significant antitumor activity and inhibits ovarian cancer progression by regulating the APC-SMAD4-CTLA-4 molecular axis. This study lays an important theoretical foundation for the development of novel antitumor drugs based on AN02, with significant clinical application potential. However, the long-term toxicity and safety of AN02 require further investigation to establish safe dosage standards for clinical use. Future studies will focus on exploring combination therapy strategies of AN02 in cisplatin-resistant ovarian cancer to provide new directions for precision treatment of ovarian cancer.

Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disease characterized by the degeneration of motor neurons and the pathological accumulation of phosphorylated TDP-43. Casein kinase one delta (CK1) has been identified as a key regulator of this aberrant phosphorylation, making it a promising therapeutic target. In this theoretical study, 26 structurally diverse compounds were evaluated against CK1 using molecular docking, molecular dynamics simulations, and binding free energy calculations. Among them, BZH exhibited the most stable interaction with CK1 ( kcal/mol). An inverse correlation was observed between theoretical affinity and experimental IC50 values, supporting the predictive validity of the computational approach. Pharmacokinetic analysis indicated that IMF and BIP show good oral absorption and the ability to cross the blood–brain barrier. At the same time, the toxicological profile classified all compounds in toxicity Class IV (moderate risk). Additionally, dynamic migration toward an alternative pocket was observed during simulation, highlighting the importance of considering protein flexibility in drug design. This study proposes BZH, IMF, and BIP as promising CK1 inhibitors for future experimental validation in the treatment of ALS.

ADME profile of BZP (benzylpiperazine) - first application of multi-in silico approach methodology for comprehensive prediction of ADME profile (absorption, distribution, metabolism and excretion) important for clinical toxicology and forensic purposes.

The purpose of this study was to investigate the theoretical and in vitro experimental prediction of food effects on oral drug absorption, focusing on solubility-epithelial membrane permeation-limited cases (SL-E). Bosentan, fidaxomicin, pranlukast, and rifaximin were employed as model SL-E drugs. Celecoxib and danazol were employed as solubility-unstirred water layer permeation-limited cases (SL-U) for comparison. Theoretical predictions of food effects were based on the rate-limiting steps of the fraction of a dose absorbed (Fa) (FaRLS) (Fa rate-limiting step). μFLUX was used as a dissolution-permeation flux (JμFLUX) experiment. Fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF, respectively) were employed as the donor solution. For all SL-E drugs, the food effect on Fa was theoretically predicted to be 1.2, irrespective of bile micelle solubilization (FaSSIF/FeSSIF: bosentan (2.1), fidaxomicin (2.3), pranlukast (9.1), and rifaximin (3.5)). Theoretically, an increase in solubility by bile micelles is counterbalanced by a decrease in effective permeability (Peff) due to a decrease in the free fraction (Peff is defined based on unbound + bound drug concentration (CD)). This prediction was consistent with the clinical data (fed/fasted AUC ratio: 1.1, 1.0, 1.3, and 1.6, respectively). In μFlux, even though CD was markedly higher in FeSSIF than in FaSSIF (1.9, 3.1, 20, and 3.3-fold, respectively), JμFLUX was less enhanced (0.91, 0.81, 2.4, and 0.81-fold, respectively). For the SL-U drugs, as theoretically expected, JμFLUX was increased as CD was increased, which was consistent with the clinical data. FaRLS appropriately predicted the food effect for the SL-E drugs. The mechanism was experimentally confirmed by μFlux.

Design, synthesis, and evaluation of novel quinazoline derivatives as potent EGFR inhibitors: In silico and in vitro approaches.

Balancing oral sequential absorption barriers of semaglutide-loaded nanoparticles by optimization of surface glycocholic acid density.

Purpose: Tizanidine (TNZ) is a muscle relaxant that works by blocking presynaptic neurons. Due to its inadequate solubility and low oral bioavailability, this medication is classified as a Biopharmaceutics Classification System (BCS) class II drug. The objective of this study was to improve the absorption of TNZ using nanostructured lipid nanoparticles (NLCs) as a method of delivering the medicine. Methods: To achieve this objective, NLCs were synthesized using microemulsion techniques. The optimization process was conducted using Design Expert version 12 Box Behnken model. The parameters of interest were mean particle size (PS), zeta potential (ZP), and percent entrapment efficiency (EE%). The concentrations of the medication, lipid, and surfactant were varied during the optimization process. Further characterization included Fourier transform infrared Spectroscopy (FTIR) and powdered X-ray diffraction (PXRD). The optimized formulation was subsequently tested for in-vitro release under varying pH conditions. The pharmacokinetic study was elicited to assess the oral bioavailability of the TNZ-NLCs in comparison to its suspension. Results: The formulation was tuned to have PS of 208 nm, a polydispersity index (PDI) of 0.221, a ZP of -18.6 mV, and an EE% of 93%. The optimized formulation remained physically stable for 12 weeks under various temperatures. The pharmacokinetic study indicated a 21-fold enhancement in AUC due to entrapment of TNZ into NLCs thereby, aligning with the aim to improve bioavailability. Conclusion: It was inferred that the inclusion of TNZ within NLCs results in its controlled release with enhanced bioavailability.

Lipid-based formulations can enhance the oral absorptionof poorlywater-soluble drugs. Their performance is typically evaluated by invitro lipolysis. For this, samples are usually prepared by centrifugation,and formulation performance is evaluated based on the concentrationin the aqueous phase. However, several studies have questioned thepredictiveness of the in vitro lipolysis method. A reason for thein vitro-in vivo mismatch may be that centrifugation cannot separatetruly dissolved drug molecules from molecules associated with colloidalassemblies such as mixed micelles. The present study tested microdialysisas an alternative sampling technique for in vitro lipolysis by whichtruly dissolved drug molecules (i.e., the free fraction) can be separatedfrom colloid-associated drug molecules. Thereby, a better mechanisticunderstanding of the formulation performance will possibly be achieved.Indomethacin and a medium-chain type IIIB lipid-based formulationwere used as model drug and model formulation, respectively. Microdialysissampling was found compatible with lipolysis medium with bile salts,phospholipids, and pancreatic enzymes. In a proof-of-concept study,microdialysis provided near-real-time concentrations of free indomethacinduring the in vitro lipolysis process and revealed supersaturationof indomethacin. However, indomethacin supersaturation was also observedunder nonlipolytic conditions. Based on microdialysis data, digestionwould not influence the formulation performance. In contrast, conventionalsamples showed that lipolysis significantly decreased the solubilizationcapacity of the formulation. Other examples have been described inthe literature where oral absorption from lipid-based formulationshad been independent of digestion even though data from in vitro lipolysiswith conventional sampling indicated the opposite. Overall, microdialysisis a promising and complementary sampling technique for the evaluationof lipid-based formulations by in vitro lipolysis.