Chlorogenic Acid: A Systematic Review on the Biological Functions, Mechanistic Actions, and Therapeutic Potentials.

Chlorogenic acid (CGA) is a type of polyphenol compound found in rich concentrations in many plants such as green coffee beans. As an active natural substance, CGA exerts diverse therapeutic effects in response to a variety of pathological challenges, particularly conditions associated with chronic metabolic diseases and age-related disorders. It shows multidimensional functions, including neuroprotection for neurodegenerative disorders and diabetic peripheral neuropathy, anti-inflammation, anti-oxidation, anti-pathogens, mitigation of cardiovascular disorders, skin diseases, diabetes mellitus, liver and kidney injuries, and anti-tumor activities. Mechanistically, its integrative functions act through the modulation of anti-inflammation/oxidation and metabolic homeostasis. It can thwart inflammatory constituents at multiple levels such as curtailing NF-kB pathways to neutralize primitive inflammatory factors, hindering inflammatory propagation, and alleviating inflammation-related tissue injury. It concurrently raises pivotal antioxidants by activating the Nrf2 pathway, thus scavenging excessive cellular free radicals. It elevates AMPK pathways for the maintenance and restoration of metabolic homeostasis of glucose and lipids. Additionally, CGA shows functions of neuromodulation by targeting neuroreceptors and ion channels. In this review, we systematically recapitulate CGA's pharmacological activities, medicinal properties, and mechanistic actions as a potential therapeutic agent. Further studies for defining its specific targeting molecules, improving its bioavailability, and validating its clinical efficacy are required to corroborate the therapeutic effects of CGA.

Self-Assembled Nanoparticles from Xie-Bai-San Decoction: Isolation, Characterization and Enhancing Oral Bioavailability.

Background: Natural nanoparticles have been found to exist in traditional Chinese medicine (TCM) decoctions. However, whether natural nanoparticles can influence the oral bioavailability of active compounds has not been elucidated. Using Xie-Bai-San decoction (XBSD) as an example, the purpose of this study was to isolate, characterize and elucidate the mechanism of the nanoparticles (N-XBSD) in XBSD, and further to explore whether the bioavailability of the main active compounds could be enhanced by N-XBSD. Methods: N-XBSD were isolated from XBSD, and investigated its characterization and study of its formation mechanism, and evaluation of its ability to enhance bioavailability of active compounds. Results: The N-XBSD was successfully isolated with the average particle size of 104.53 nm, PDI of 0.27 and zeta potential of -5.14 mV. Meanwhile, all the eight active compounds were most presented in N-XBSD. Kukoamine B could self-assemble with mulberroside A or liquiritin to form nanoparticles, respectively. And the FT-IR and HRMS results indicated the possible binding of the ammonium group of kukoamine B with the phenolic hydroxyl group of mulberroside A or liquiritin, respectively. The established UPLC-MS/MS method was accurate and reliable and met the quantitative requirements. The pharmacokinetic behaviors of the N-XBSD and decoction were similar in rats. Most notably, compared to that of free drugs, the Cmax, AUC0-∞, AUC0-t, T1/2 and MRT0-∞ values of index compounds were the higher in N-XBSD, with a slower plasma clearance rate in rats. Conclusion: The major active compounds of XBSD were mainly distributed in N-XBSD, and N-XBSD was formed through self-assembly among active compounds. N-XBSD could obviously promote the bioavailability of active compounds, indicating natural nanoparticles of decoctions play an important role in therapeutic effects.

Microbial phosphorus-cycling genes in soil under global change.

The ongoing climate change on the Tibetan Plateau, leading to warming and precipitation anomalies, modifies phosphorus (P) cycling in alpine meadow soils. However, the interactions and cascading effects of warming and precipitation changes on the key "extracellular" and "intracellular" P cycling genes (PCGs) of bacteria are largely unknown for these P-limited ecosystems. We used metagenomics to analyze the individual and combined effects of warming and altered precipitation on soil PCGs and P transformation in a manipulation experiment. Warming and increased precipitation raised Olsen-P (bioavailable P, AP) by 13% and 20%, respectively, mainly caused by augmented hydrolysis of organic P compounds (NaOH-Po). The decreased precipitation reduced soil AP by 5.3%. The richness and abundance of the PCGs' community in soils on the cold Tibetan plateau were more sensitive to warming than altered precipitation. The abundance of PCGs and P cycling processes decreased under the influence of individual climate change factors (i.e., warming and altered precipitation alone), except for the warming combined with increased precipitation. Pyruvate metabolism, phosphotransferase system, oxidative phosphorylation, and purine metabolism (all "intracellular" PCG) were closely correlated with P pools under climate change conditions. Specifically, warming recruited bacteria with the phoD and phoX genes, which encode enzymes responsible for phosphoester hydrolysis (extracellular P cycling), strongly accelerated organic P mineralization and so, directly impacted P bioavailability in alpine soil. The interactions between warming and altered precipitation profoundly influenced the PCGs' community and facilitated microbial adaptation to these environmental changes. Warming combined with increased precipitation compensated for the detrimental impacts of the individual climate change factors on PCGs. In conclusion, warming combined with rising precipitation has boosting effect on most P-related functions, leading to the acceleration of P cycling within microbial cells and extracellularly, including mineralization and more available P release for microorganisms and plants in alpine soils.

Anionic Methacrylate Copolymer Microparticles for the Delivery of Myo-Inositol Produced by Spray-Drying: In Vitro and In Vivo Bioavailability.

In this study, a new micro delivery system based on an anionic methacrylate copolymer, able to improve the biological response of myo-inositol by daily oral administration, was manufactured by spray-drying. It has an ideal dose form for oral administration, with an experimental drug loading (DL)% of 14% and a regulated particle size of less than 15 µm. The new formulation features an improvement on traditional formulations used as a chronic therapy for the treatment of polycystic ovary syndrome. The microparticles' release profile was studied and ex vivo porcine intestinal mucosa permeation experiments were performed to predict potential improvements in oral absorption. Batch n. 3, with the higher Eudragit/MI weight ratio (ratio = 6), showed the best-modified release profiles of the active ingredient, ensuring the lowest myo-inositol loss in an acidic environment. The in vivo evaluation of the myo-inositol micro delivery system was carried out in a rat animal model to demonstrate that the bioavailability of myo-inositol was increased when compared to the administration of the same dosage of the pure active ingredient. The AUC and Cmax of the loaded active molecule in the micro delivery system was improved by a minimum of 1.5 times when compared with the pure substance, administered with same dosage and route. Finally, the increase of myo-inositol levels in the ovary follicles was assessed to confirm that a daily administration of the new formulation improves myo-inositol concentration at the site of action, resulting in an improvement of about 1.25 times for the single administration and 1.66 times after 7 days of repeated administration when compared to pure MI.

In Vivo Absorption and Lymphatic Bioavailability of Docosahexaenoic Acid from Microalgal Oil According to Its Physical and Chemical Form of Vectorization.

Docosahexaenoic acid (DHA) is an essential fatty acid (FA) with proven pro-health effects, but improving its bioavailability is becoming a public health issue. The bioavailability of DHA from microalgal (A) oil has been comprehensively assessed, particularly in terms of the molecular structuring capabilities offered by A-oil. Here, we explored the impact of five DHA-rich formulas differing in terms of (i) molecular structure, i.e., ethyl ester (EE), monoglyceride (MG), or triglyceride (TG), and (ii) supramolecular form, i.e., emulsified TG or TG + phospholipids (PL blend) on the lymphatic kinetics of DHA absorption and the lipid characteristics of the resulting lipoproteins. We demonstrated in rats that the conventional A-DHA TG structure afforded more effective DHA absorption than the EE structure (+23%). Furthermore, the A-DHA MG and A-DHA emulsions were the better DHA vectors (AUC: 89% and +42%, respectively) due to improved lipolysis. The A-DHA MG and A-DHA emulsion presented the richest DHA content in TG (+40%) and PL (+50%) of lymphatic chylomicrons, which could affect the metabolic fate of DHA. We concluded that structuring A-DHA in TG or EE form would better serve for tissue and hepatic metabolism whereas A-DHA in MG and emulsion form could better target nerve tissues.

In Vitro Evaluation of Bioavailability of Cr from Daily Food Rations and Dietary Supplements from the Polish Market.

Only some of the nutrients consumed with food are able to be absorbed from the gastrointestinal (GI) tract and enter the systemic circulation (blood). Because some elements are essential minerals for humans, their beneficial effect on the body depends significantly on their bioavailable amount (the fraction that can be absorbed and used by the organism). The term bioavailability, which is very often used to describe the part of nutrients that is able to be absorbed, is influenced by various factors of exogenous and endogenous origin. The main purpose of the study was to assess the relative bioavailability of Cr from selected dietary supplements in the presence of various types of diets, which significantly influence the level of bioavailability. The research was performed using a previously developed and optimized two-stage in vitro digestion model using cellulose dialysis tubes of food rations with the addition of pharmaceutical products. Cr was determined using the ICP-OES and GF-AAS methods, depending on its concentration in particular fractions. The determined relative bioavailability ranged between 2.97 and 3.70%. The results of the study revealed that the type of diet, the chemical form of the molecule, and the pharmaceutical form of preparations have a significant influence on the bioavailability of Cr.

Non-Invasive Delivery of Insulin for Breaching Hindrances against Diabetes.

Insulin is recognized as a crucial weapon in managing diabetes. Subcutaneous (s.c.) injections are the traditional approach for insulin administration, which usually have many limitations. Numerous alternative (non-invasive) slants through different routes have been explored by the researchers for making needle-free delivery of insulin for attaining its augmented absorption as well as bioavailability. The current review delineating numerous pros and cons of several novel approaches of non-invasive insulin delivery by overcoming many of their hurdles. Primary information on the topic was gathered by searching scholarly articles from PubMed added with extraction of data from auxiliary manuscripts. Many approaches (discussed in the article) are meant for the delivery of a safe, effective, stable, and patient friendly administration of insulin via buccal, oral, inhalational, transdermal, intranasal, ocular, vaginal and rectal routes. Few of them have proven their clinical efficacy for maintaining the glycemic levels, whereas others are under the investigational pipe line. The developed products are comprising of many advanced micro/nano composite technologies and few of them might be entering into the market in near future, thereby garnishing the hopes of millions of diabetics who are under the network of s.c. insulin injections.

Modeling the subcutaneous pharmacokinetics of antibodies co-administered with rHuPH20.

Predicting the subcutaneous (SC) pharmacokinetics (PK) of antibodies in humans is challenging, with clinical data currently being the only reliable data source for modeling SC absorption and bioavailability. Recombinant human hyaluronidase PH20 (rHuPH20) is an enzyme that facilitates SC delivery of high-dose, high-volume therapeutics. Numerous monoclonal antibodies have been co-administered SC with rHuPH20 in a clinical setting, establishing an extensive PK database. The goal of this work is to demonstrate how aggregated clinical data can be leveraged in a universal modeling framework for characterizing SC antibody PK, resulting in parameterization that can be used in predictive simulations of new antibodies. Data for 10 individual antibodies co-administered SC with rHuPH20 were obtained from publicly available sources. PK modeling of each antibody was conducted using the same model structure, but uniquely parameterized. The model structure consisted of a two-compartment model to capture linear kinetics, plus a target-binding mechanism to accommodate nonlinear kinetics driven by antibody-target complex formation and elimination. The clinical PK profiles for all antibodies were accurately described using the universal modeling framework. The SC PK parameters of absorption and bioavailability were consistent across the range of antibody and target properties evaluated. SC administration with rHuPH20 yielded a 30% increase in absorption rate on average and similar or better bioavailability. These parameter values can serve as initial conditions for model-based PK predictions for new antibodies co-administered SC with rHuPH20 to enable evaluation of optimal SC dose and schedule regimens prior to and during clinical development.

Natural Amino Acid-Bearing Carbamate Prodrugs of Daidzein Increase Water Solubility and Improve Phase II Metabolic Stability for Enhanced Oral Bioavailability.

Daidzein (DAN) is an isoflavone, and it is often found in its natural form in soybean and food supplements. DAN has poor bioavailability owing to its extremely low water solubility and first-pass metabolism. Herein, we hypothesized that a bioactivatable natural amino acid-bearing carbamate prodrug strategy could increase the water solubility and metabolic stability of DAN. To test our hypothesis, nine amino acid prodrugs of DAN were designed and synthesized. Compared with DAN, the optimal prodrug (daidzein-4'-O-CO-N-isoleucine, D-4'-I) demonstrated enhanced water solubility and improved phase II metabolic stability and activation to DAN in plasma. In addition, unlike the passive transport of DAN, D-4'-I maintained high permeability via organic anion-transporting polypeptide 2B1 (OATP2B1)-mediated transport. Importantly, D-4'-I increased the oral bioavailability by 15.5-fold, reduced the gender difference, and extended the linear absorption capacity in the pharmacokinetics of DAN in rats. Furthermore, D-4'-I exhibited dose-dependent protection against liver injury. Thus, the natural amino acid-bearing carbamate prodrug strategy shows potential in increasing water solubility and improving phase II metabolic stability to enhance the oral bioavailability of DAN.

Bioavailability and Metabolism of Bioactive Peptide IRW with Angiotensin-Converting Enzyme 2 (ACE2) Upregulatory Activity in Spontaneously Hypertensive Rats.

Peptide IRW is the first food-derived angiotensin-converting enzyme 2 (ACE2) upregulator. This study aimed to investigate the pharmacokinetic characteristics of IRW and identify the metabolites contributing to its antihypertensive activity in spontaneously hypertensive rats (SHRs). Rats were administered 100 mg of IRW/kg of the body weight via an intragastric or intravenous route. The bioavailability (F %) was determined to be 11.7%, and the half-lives were 7.9 ± 0.5 and 28.5 ± 6.8 min for gavage and injection, respectively. Interestingly, significant blood pressure reduction was not observed until 1.5 h post oral administration, or 2 h post injection, indicating that the peptide's metabolites are likely responsible for the blood pressure-lowering activity. Time-course metabolomics revealed a significant increase in the level of kynurenine, a tryptophan metabolite, in blood after IRW administration. Kynurenine increased the level of ACE2 in cells. Oral administration of tryptophan (W), but not dipeptide IR, lowered the blood pressure and upregulated aortic ACE2 in SHRs. Our study supports the key role of tryptophan and its metabolite, kynurenine, in IRW's blood pressure-lowering effects.

Pharmacokinetics of L-theanine and the effect on amino acid composition in mice administered with L-theanine.

L-theanine, an amino acid component of the tea leaves of Camellia sinensis, is sold in Japan as a supplement for good sleep. Although several studies in humans and mice have reported the effects of L-theanine on brain function, only a few reports have comprehensively clarified the disposition of theanine administered to mice and its effects on concentrations of other blood amino acids. In this study, we aimed to determine the changes in the blood levels of L-theanine administered to mice and amino acid composition of the serum. L-theanine were administered to four-week-old Std-ddY male mice orally or via tail vein injection. L-theanine and other amino acids in serum prepared from blood collected at different time points post-dose were labeled with phenylisothiocyanate and quantified. The serum concentration of orally administered L-theanine peaked 15 min after administration. The area under the curve for tail vein injection revealed the bioavailability of L- theanine to be approximately 70%. L-theanine administration did not affect any amino acid levels in the serum, but a significant increase in the peak area overlapping the Glycine (Gly) peak was observed 30 min after administration. L-theanine administered to mice was rapidly absorbed and eliminated, suggesting that taking L-theanine as a supplement is safe without affecting its own levels or serum levels of other amino acids. However, considering that Gly, similar to L-theanine, is used as a dietary supplement for its anxiolytic effects and to improve sleep, determining the effects of L-theanine administration on Gly is important and needs further research.

Arsenic Exposure-Related Hypertension in Bangladesh and Reduced Circulating Nitric Oxide Bioavailability.

BACKGROUND: Hypertension is a major cause of death worldwide. Although arsenic exposure has been associated with the risk of hypertension, this association appears nonuniform due to inconsistent results from studies conducted in different populations. Moreover, hypertension is a complex condition with multiple underlying mechanisms and factors. One factor is impaired production and bioavailability of vascular nitric oxide (NO). However, the implications of the effects of arsenic exposure on circulating NO and its association with hypertension in humans are largely unknown. OBJECTIVE: We investigated the dose-response relationship between arsenic exposure and hypertension with vascular NO levels as a potential mediator of arsenic-related hypertension in individuals exposed to a broad range of arsenic. METHODS: A total of 828 participants were recruited from low- and high-arsenic exposure areas in Bangladesh. Participants' drinking water, hair, and nail arsenic concentrations were measured by inductively coupled plasma mass spectroscopy. Hypertension was defined as a systolic blood pressure (SBP) value of ≥140 and a diastolic (DBP) value of ≥90 mmHg. Serum NO levels reflected by total serum nitrite concentrations were measured by immunoassay. A formal causal mediation analysis was used to assess NO as a mediator of the association between arsenic level and hypertension. RESULTS: Increasing concentrations of arsenic measured in drinking water, hair, and nails were associated with the increasing levels of SBP and DBP. The odds of hypertension were dose-dependently increased by arsenic even in participants exposed to relatively low to moderate levels (10-50µg/L) of water arsenic [odds ratios (ORs) and 95% confidence intervals (CIs): 2.87 (95% CI: 1.28, 6.44), 2.67 (95% CI: 1.27, 5.60), and 5.04 (95% CI: 2.71, 9.35) for the 10-50µg/L, 50.01-150µg/L, and >150µg/L groups, respectively]. Causal mediation analysis showed a significant mediating effect of NO on arsenic-related SBP, DBP, and hypertension. CONCLUSION: Increasing exposure to arsenic was associated with increasing odds of hypertension. The association was mediated through the reduction of vascular NO bioavailability, suggesting that impaired NO bioavailability was a plausible underlying mechanism of arsenic-induced hypertension in this Bangladeshi population. https://doi.org/10.1289/EHP13018.

Self-micellizing solid dispersion of thymoquinone with enhanced biopharmaceutical and nephroprotective effects.

The present study was designed to develop a self-micellizing solid dispersion (SMSD) containing Thymoquinone (TQM), a phytonutrient obtained from Nigella sativa seeds, aiming to improve its biopharmaceutical and nephroprotective functions. The apparent solubility of TQM in polymer solutions was used to choose an appropriate amphiphilic polymer that could be used to make an SMSD system. Based on the apparent solubility, Soluplus® was selected as an appropriate carrier, and mixing with TQM, SMSD-TQM with different loadings of TQM (5-15%) was made by solvent evaporation and freeze-drying techniques, respectively, and the formulations were optimized. The optimized SMSD-TQM was evaluated in terms of particle size distribution, morphology, release characteristics, pharmacokinetic behavior, and nephroprotective effects in a rat model of acute kidney injury. SMSD-TQM significantly improved the dissolution characteristics (97.8%) of TQM in water within 60 min. Oral administration of SMSD-TQM in rats exhibited a 4.9-fold higher systemic exposure than crystalline TQM. In a cisplatin-induced (6 mg/kg, i.p.) acute kidney-damaged rat model, oral SMSD-TQM (10 mg/kg) improved the nephroprotective effects of TQM based on the results of kidney biomarkers and histological abnormalities. These findings suggest that SMSD-TQM might be efficacious in enhancing the nephroprotective effect of TQM by overcoming biopharmaceutical limitations.

Nutraceutically-enhanced oral delivery of vitamin D3 via Bio-SNEDDS: Demonstrating in vivo superiority over pediatric formulations.

BACKGROUND: Vitamin D3 (VD3) deficiency among children in Saudi Arabia remains a pressing concern due to its poor bioavailability and the limitations of current pediatric formulations. To address this challenge, we developed a groundbreaking pediatric self-nanoemulsifying drug delivery system (Bio-SNEDDS) for VD3, fortified with black seed oil and moringa seed oil for dual therapeutic benefits. Through meticulous formulation optimization using ternary phase diagrams and comprehensive testing, our Bio-SNEDDS demonstrated exceptional performance. METHODS: Bio-SNEDDS were manufactured by incorporating Black seed oil and moringa seed oil as bioactive nutraceutical excipients along with various cosurfactant and surfactants. Bio-SNEDDS were systematically optimized through ternary phase diagrams, visual tests, droplet size analysis, drug solubilization studies, dispersion assessments, and pharmacokinetic testing in rats compared to Vi-De 3®. RESULTS: Pseudoternary phase diagrams identified oil blends producing large nanoemulsion regions optimal for SNEDDS formation. The optimized F1 Bio-SNEDDS showed a mean droplet diameter of 33.7 nm, solubilized 154.46 mg/g VD3 with no metabolite formation, and maintained >88% VD3 in solution during 24 h dispersion testing. Notably, in vivo pharmacokinetic evaluation at a high VD3 dose demonstrated an approximately two-fold greater relative bioavailability over Vi-De 3®, validating the superb oral delivery performance of Bio-SNEDDS even under challenging high-dose conditions. CONCLUSIONS: The Bio-SNEDDS provides an effective VD3 delivery strategy with established in vivo superiority over marketed products, along with offering additional health benefits from the natural oils.

Measuring bioavailability, utilization, and excretion of rumen-protected lysine in lactating cows using an isotope technique.

Supplementing a diet with rumen-protected amino acids (AAs) is a common feeding strategy for efficient production. For a cost-effective use of rumen-protected AA, the accurate bioavailability of rumen-protected amino acids should be known and their metabolism after absorption needs to be well understood. The current study determined the bioavailability, absorption, utilization, and excretion of rumen-protected Lys (RP-Lys). Four ruminally cannulated cows in a 4 × 4 Latin square design (12 d for diet adaptation; 5 or 6 d for total collections) received the following treatments: L0, a basal diet; L25, the basal diet and L-Lys infused into the abomasum to provide 25.9 g/d L-Lys; L50, the basal diet and L-Lys infused into the abomasum to provide 51.8 g/d L-Lys; and RPL, the basal diet supplemented with 105 g/d (as-is) of RP-Lys to provide 26.7 g of digestible Lys. During the last 5 or 6 d in each period, 15N-Lys (0.38 g/d) was infused into the abomasum for all cows to label the pool of AA, and the total collection of milk, urine, and feces were conducted. 15N enrichment of samples on d 4 and 5 were used to calculate the bioavailability and Lys metabolism. We used a model containing a fast AA turnover (≤ 5 d) and slow AA turnover pool (> 5 d) to calculate fluxes of Lys. The Lys flux to the fast AA turnover pool (absorbed Lys + Lys from the slow AA turnover pool to fast AA turnover pool) was calculated using 15N enrichment of milk Lys. The flux of Lys from the fast AA turnover pool to milk and urine was calculated using 15N transfer into milk and urine. Then, absorbed Lys was estimated by the sum of Lys flux to milk and urine assuming no net utilization of Lys by body tissues. Duodenal Lys flow was estimated by 15N enrichment of fecal Lys. The bioavailability of RP-Lys was calculated from duodenal Lys flows and Lys absorption for RPL. Increasing Lys supply from L25 to L50 increased Lys utilization for milk by 9 g/d but also increased urinary excretion by 10 g/d. For RPL, absorbed Lys was estimated to be 136 g/d where 28 g of absorbed Lys originated from RP-Lys. In conclusion, 68% of bioavailability was obtained for RP-Lys. The Lys provided from RP-Lys was not only utilized for milk protein (48%) but also excreted in urine (20%) after oxidation.

Recent developments in the use of nanocrystals to improve bioavailability of APIs.

Nanocrystals refer to materials with at least one dimension smaller than 100 nm, composing of atoms arranged in single crystals or polycrystals. Nanocrystals have significant research value as they offer unique advantages over conventional pharmaceutical formulations, such as high bioavailability, enhanced targeting selectivity and controlled release ability and are therefore suitable for the delivery of a wide range of drugs such as insoluble drugs, antitumor drugs and genetic drugs with broad application prospects. In recent years, research on nanocrystals has been progressively refined and new products have been launched or entered the clinical phase of studies. However, issues such as safety and stability still stand that need to be addressed for further development of nanocrystal formulations, and significant gaps do exist in research in various fields in this pharmaceutical arena. This paper presents a systematic overview of the advanced development of nanocrystals, ranging from the preparation approaches of nanocrystals with which the bioavailability of poorly water-soluble drugs is improved, critical properties of nanocrystals and associated characterization techniques, the recent development of nanocrystals with different administration routes, the advantages and associated limitations of nanocrystal formulations, the mechanisms of physical instability, and the enhanced dissolution performance, to the future perspectives, with a final view to shed more light on the future development of nanocrystals as a means of optimizing the bioavailability of drug candidates. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Dissolution and antioxidant potential of apigenin self nanoemulsifying drug delivery system (SNEDDS) for oral delivery.

Self-nanoemulsifying drug delivery systems (SNEDDS) have been used to improve the oral bioavailability of various drugs. In the current study, apigenin was developed as SNEDDS to solve its dissolution problem and enhance oral bioavailability and antioxidant potential. SNEDDS were prepared by mixing Gelucire 44/14, Tween 80, and PEG 400 under controlled conditions. The droplet of diluted SNEDDS demonstrated a spherical shape with a size of less than 100 nm and a neutral charge. The very fast self-emulsification was obtained within 32 s, and the transmittance values exceeded 99%. The highest drug loading was 90.10 ± 0.24% of the initial load with the highest %encapsulation efficiency of 84.20 ± 0.03%. FT-IR and DSC spectra showed no interaction between components. The dissolution in buffer pH 1.2, 4.5, and 6.8 showed significantly higher dissolved apigenin than the apigenin coarse powder. The dissolution profiles were fitted to the Korsmeyer-Peppas kinetics. The cellular antioxidant activities in Caco-2 cells were approximately 52.25-54.64% compared to no treatment and were higher than the apigenin coarse powder (12.70%). Our work highlights the potential of SNEDDS to enhance the dissolution and permeability of apigenin and promote antioxidant efficacy, which has a strong chance of being developed as a bioactive compound for nutraceuticals.

Gender difference in the pharmacokinetics and metabolism of VX-548 in rats.

VX-548 is a sodium channel blocker, which acts as an analgesic. This study aims to investigate the gender differences in the pharmacokinetics and metabolism of VX-548 in rats. After intravenous administration, the area under the curve (AUC0-t) of VX-548 was much higher in female rats (1505.8 ± 47.3 ng·h/mL) than in male rats (253.8 ± 6.3 ng·h/mL), and the clearance in female rats (12.5 ± 0.8 mL/min/kg) was much lower than in male rats (65.1 ± 1.7 mL/min/kg). After oral administration, the AUC0-t in female rats was about 50-fold higher than that in male rats. The oral bioavailability in male rats was 11% while it was 96% in female rats. An in vitro metabolism study revealed that the metabolism of VX-548 in female rat liver microsomes was much slower than in male rats. Further metabolite identification suggested that the significant gender difference in pharmacokinetics was attributed to demethylation. The female rat liver microsomes showed a limited ability to convert VX-548 into desmethyl VX-548. Phenotyping experiments indicated that the formation of desmethyl VX-548 was mainly catalyzed by CYP3A2 and CYP2C11 using rat recombinant CYPs. Overall, we revealed that the pharmacokinetics and metabolism of VX-548 in male and female rats showed significant gender differences.

Enhanced Solubility and Bioavailability of Clotrimazole in Aqueous Solutions with Hydrophobized Hyperbranched Polyglycidol for Improved Antifungal Activity.

The poor solubility of clotrimazole in the aqueous medium and the uncontrolled removal of the drug-loaded suppository content limit its effectiveness in the treatment of vulvovaginal candidiasis. We present here the aqueous formulations of clotrimazole in the form of non-Newtonian structured fluids, i.e., Bingham plastic or pseudoplastic fluids constructed of hyperbranched polyglycidol, HbPGL, with a hydrophobized core with aryl groups such as phenyl or biphenyl. The amphiphilic constructs were obtained by the modification of linear units containing monohydroxyl groups with benzoyl chloride, phenyl isocyanate, and biphenyl isocyanate, while the terminal 1,2-diol groups in the shell were protected during the modification step, followed by their deprotection. The encapsulation of clotrimazole within internally hydrophobized HbPGLs using a solvent evaporation method followed by water addition resulted in structured fluids formation. Detailed Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) analyses performed for aryl-HbPGLs with clotrimazole revealed the difference in drug compatibility among polymers. Clotrimazole in biphenyl-enriched HbPGL, unlike phenyl derivatives, was molecularly distributed in both the dry and the hydrated states, resulting in transparent formulations. The shear-thinning properties of the obtained fluid formulations make them injectable and thus suitable for the intravaginal application. Permeability tests performed with the usage of the Franz diffusion cell showed a 5-fold increase in the permeability constant of clotrimazole compared to drugs loaded in a commercially available disposable tablet and a 50-fold increase of permeability in comparison to the aqueous suspension of clotrimazole. Furthermore, the biphenyl-modified HbPGL-based drug liquid showed enhanced antifungal activity against both Candida albicans and Candida glabrata that was retained for up to 7 days, in contrast to the phenyl-HbPGL derivatives and the tablet. With their simple formulation, convenient clotrimazole/biphenyl-HbPGL formulation strategy, rheological properties, and enhanced antifungal properties, these systems are potential antifungal therapeutics for gynecological applications. This study points in the synthetic direction of improving the solubility of poorly water-soluble aryl-enriched pharmaceuticals.