scholarly journals In Silico Analysis and Experimental Evaluation of Ester Prodrugs of Ketoprofen for Oral Delivery: With a View to Reduce Toxicity

Processes ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 2221
Author(s):  
Kishor Mazumder ◽  
Md. Emran Hossain ◽  
Asma Aktar ◽  
Mohammad Mohiuddin ◽  
Kishore Kumar Sarkar ◽  
...  
Keyword(s):  
In Silico ◽  
Oral Delivery ◽  
Oral Absorption ◽  
Oral Treatment ◽  
Prolonged Treatment ◽  
Spectrometric Analysis ◽  
Peripheral Stimulus ◽  
Methyl Derivative ◽  
Ester Prodrugs

The present research aimed to synthesize ketoprofen prodrugs and to demonstrate their potentiality for oral treatment to treat chronic inflammation by reducing its hepatotoxicity and gastrointestinal irritation. Methyl 2-(3-benzoyl phenyl) propanoate, ethyl 2-(3-benzoyl phenyl) propanoate and propyl 2-(3-benzoyl phenyl) propanoate was synthesized by esterification and identified by nuclear magnetic resonance (1HNMR) and infrared (IR) spectrometric analysis. In silico SwissADME and ProTox-II analysis stated methyl derivative as ideal candidate for oral absorption, having a >30-fold LD50 value compared to ketoprofen with no hepatotoxicity. Moreover, in vivo hepatotoxicity study demonstrates that these ester prodrugs have significantly lower effects on liver toxicity compared to pure ketoprofen. Furthermore, ex vivo intestinal permeation enhancement ratio was statistically significant (* p < 0.05) compared to ketoprofen. Likewise, the prodrugs were found to exhibit not only remarkable in vitro anti-proteolytic and lysosomal membrane stabilization potentials, but also significant efficiency to alleviate pain induced by inflammation, as well as central and peripheral stimulus in mice model in vivo. These outcomes recommend that ketoprofen ester prodrugs, especially methyl derivative, can be a cost-effective candidate for prolonged treatment of chronic inflammatory diseases.

scholarly journals Predicting Absorption-Distribution Properties of Neuroprotective Phosphine-Borane Compounds Using In Silico Modeling and Machine Learning

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2505
Author(s):  
Raheem Remtulla ◽  
Sanjoy Kumar Das ◽  
Leonard A. Levin
Keyword(s):  
Machine Learning ◽  
Neural Networks ◽  
In Silico ◽  
Disulfide Bonds ◽  
Oral Absorption ◽  
In Vivo Studies ◽  
Drug Candidates ◽  
In Silico Methods

Phosphine-borane complexes are novel chemical entities with preclinical efficacy in neuronal and ophthalmic disease models. In vitro and in vivo studies showed that the metabolites of these compounds are capable of cleaving disulfide bonds implicated in the downstream effects of axonal injury. A difficulty in using standard in silico methods for studying these drugs is that most computational tools are not designed for borane-containing compounds. Using in silico and machine learning methodologies, the absorption-distribution properties of these unique compounds were assessed. Features examined with in silico methods included cellular permeability, octanol-water partition coefficient, blood-brain barrier permeability, oral absorption and serum protein binding. The resultant neural networks demonstrated an appropriate level of accuracy and were comparable to existing in silico methodologies. Specifically, they were able to reliably predict pharmacokinetic features of known boron-containing compounds. These methods predicted that phosphine-borane compounds and their metabolites meet the necessary pharmacokinetic features for orally active drug candidates. This study showed that the combination of standard in silico predictive and machine learning models with neural networks is effective in predicting pharmacokinetic features of novel boron-containing compounds as neuroprotective drugs.

scholarly journals Antimicrobial prodrug activation by the staphylococcal glyoxalase GloB

2020 ◽  
Author(s):  
Marwa O. Mikati ◽  
Justin J. Miller ◽  
Damon M. Osbourn ◽  
Naomi Ghebremichael ◽  
Ishaan T. Shah ◽  
...  
Keyword(s):  
Oral Absorption ◽  
Loss Of Function ◽  
Prodrug Activation ◽  
Glyoxalase Ii ◽  
Human Sera ◽  
Cellular Permeability ◽  
Ester Prodrug ◽  
Ester Prodrugs

ABSTRACTWith the rising prevalence of multidrug-resistance, there is an urgent need to develop novel antibiotics. Many putative antibiotics demonstrate promising in vitro potency but fail in vivo due to poor drug-like qualities (e.g. serum half-life, oral absorption, solubility, toxicity). These drug-like properties can be modified through the addition of chemical protecting groups, creating “prodrugs” that are activated prior to target inhibition. Lipophilic prodrugging techniques, including the attachment of a pivaloyloxymethyl group, have garnered attention for their ability to increase cellular permeability by masking charged residues and the relative ease of the chemical prodrugging process. Unfortunately, pivaloyloxymethyl prodrugs are rapidly activated by human sera, rendering any membrane permeability qualities absent during clinical treatment. Identification of the bacterial prodrug activation pathway(s) will allow for the development of host-stable and microbe-targeted prodrug therapies. Here, we use two zoonotic staphylococcal species, S. schleiferi and S. pseudintermedius, to establish the mechanism of carboxy ester prodrug activation. Using a forward genetic screen, we identify a conserved locus in both species encoding the enzyme hydroxyacylglutathione hydrolase (GloB), whose loss-of-function confers resistance to carboxy ester prodrugs. We enzymatically characterize GloB and demonstrate that it is a functional glyoxalase II enzyme, which has the capacity to activate carboxy ester prodrugs. As GloB homologs are both widespread and diverse in sequence, our findings suggest that GloB may be a useful mechanism for developing species-or genus-level prodrug targeting strategies.

scholarly journals BCS Class IV Oral Drugs and Absorption Windows: Regional-Dependent Intestinal Permeability of Furosemide

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1175
Author(s):  
Milica Markovic ◽  
Moran Zur ◽  
Inna Ragatsky ◽  
Sandra Cvijić ◽  
Arik Dahan
Keyword(s):  
Intestinal Permeability ◽  
In Silico ◽  
Oral Absorption ◽  
Critical Role ◽  
Oral Drugs ◽  
Absorption Window ◽  
Low Solubility ◽  
Class Iv

Biopharmaceutical classification system (BCS) class IV drugs (low-solubility low-permeability) are generally poor drug candidates, yet, ~5% of oral drugs on the market belong to this class. While solubility is often predictable, intestinal permeability is rather complicated and highly dependent on many biochemical/physiological parameters. In this work, we investigated the solubility/permeability of BCS class IV drug, furosemide, considering the complexity of the entire small intestine (SI). Furosemide solubility, physicochemical properties, and intestinal permeability were thoroughly investigated in-vitro and in-vivo throughout the SI. In addition, advanced in-silico simulations (GastroPlus®) were used to elucidate furosemide regional-dependent absorption pattern. Metoprolol was used as the low/high permeability class boundary. Furosemide was found to be a low-solubility compound. Log D of furosemide at the three pH values 6.5, 7.0, and 7.5 (representing the conditions throughout the SI) showed a downward trend. Similarly, segmental-dependent in-vivo intestinal permeability was revealed; as the intestinal region becomes progressively distal, and the pH gradually increases, the permeability of furosemide significantly decreased. The opposite trend was evident for metoprolol. Theoretical physicochemical analysis based on ionization, pKa, and partitioning predicted the same trend and confirmed the experimental results. Computational simulations clearly showed the effect of furosemide’s regional-dependent permeability on its absorption, as well as the critical role of the drug’s absorption window on the overall bioavailability. The data reveals the absorption window of furosemide in the proximal SI, allowing adequate absorption and consequent effect, despite its class IV characteristics. Nevertheless, this absorption window so early on in the SI rules out the suitability of controlled-release furosemide formulations, as confirmed by the in-silico results. The potential link between segmental-dependent intestinal permeability and adequate oral absorption of BCS Class IV drugs may aid to develop challenging drugs as successful oral products.

Natural Furanocoumarin as Potential Oral Absorption Enhancer

2019 ◽  
Vol 819 ◽  
pp. 63-69
Author(s):  
May Phyu Thein Maw ◽  
Panadda Phattanawasin ◽  
Uthai Sotanaphun ◽  
Nusara Piyapolrungroj
Keyword(s):  
Oral Delivery ◽  
Oral Absorption ◽  
The Body ◽  
Dual Inhibitor ◽  
Active Efflux ◽  
Intestinal Membrane ◽  
Efflux Mechanism ◽  
Uptake Studies ◽  
Poor Absorption

Bioavailability of orally administered drugs can be influenced by many factors. Poor drug absorption across the intestinal membrane is one of the factors that contribute to low bioavailability of drugs. It has been suggested that the metabolism/active efflux in the small intestine is involved in the poor absorption of many drugs. Intestinal CYP3A4 and P-gp work coordinately to reduce the intracellular concentration of drugs. Recently, bioenhancers have been identified and extensively studied. The aim of this study was to evaluate natural furanocoumarins found in juices of common lime and kaffir lime as the potential enhancers for oral delivery by means of modulating CYP3A4 and/or P-gp activities. The role of isolated furanocoumarins on CYP3A4 was assessed by testosterone 6β-hydroxylation reaction, while the effect on P-gp was investigated using R123 and CAM uptake studies in Caco-2, as well as LLC-PK1 and LLC-GA5-Col300. In the present study, we demonstrated that isopimpinellin isolated from common lime is the best CYP3A4 inhibitor among 4 isolated furanocoumarins, implying that isopimpinellin would possibly act as a bioenhancer by inhibiting pre-systemic metabolism. 6’,7’-Dihydroxybergamottin found in kaffir lime is a dual inhibitor of CYP3A4 and P-gp, suggest that it could potentially be used as a bioenhancer by inhibiting both pre-systemic metabolism and efflux mechanism. However, in vivo study should be further conducted to confirm these effects in the body.

Coumarins and Quinolones as Effective Multiple Targeted Agents Versus Covid-19: An in Silico Study

2021 ◽  
Vol 17 ◽  
Author(s):  
Mojgan Nejabat ◽  
Razieh Ghodsi ◽  
Farzin Hadizadeh
Keyword(s):  
Binding Affinity ◽  
In Silico ◽  
Oral Absorption ◽  
Antiviral Agent ◽  
In Vivo Studies ◽  
Reference Drug ◽  
Viral Proteases ◽  
In Silico Study

Background: The Covid-19 virus emerged a few months ago in China and infections rapidly escalated into a pandemic. Objective: To date, there is no selective antiviral agent for the management of pathologies associated with covid-19 and the need for an effective agent against it is essential. Method: In this work two home-made databases from synthetic quinolines and coumarins were virtually docked against viral proteases (3CL and PL), human cell surface proteases (TMPRSS2 and furin) and spike proteins (S1 and S2). Chloroquine, a reference drug without a clear mechanism against coronavirus was also docked on mentioned targets and the binding affinities compared with title compounds. Result: The best compounds of synthetic coumarins and quinolines for each target were determined. All compounds against all targets showed binding affinity between -5.80 to -8.99 kcal/mol in comparison with the FDA-approved drug, Chloroquine, with binding affinity of -5.7 to -7.98 kcal/mol. Two compounds, quinoline-1 and coumarin-24, were found to be effective on three targets – S2, TMPRSS2 and furin – simultaneously, with good predicted affinity between -7.54 to -8.85 kcal/mol. In silico ADME studies also confirmed good oral absorption for them. Furthermore, PASS prediction was calculated and coumarin-24 had higher probable activity (Pa) than probable inactivity (Pi) with acceptable protease inhibitory as well as good antiviral activity against Hepatitis C virus (HCV), Human immunodeficiency virus (HIV) and influenza. Conclusion: Quinoline-1 and Coumarin-24 have the potential to be used against Covid-19. Hence these agents could be useful in combating covid-19 infection after further in vitro and in vivo studies.

scholarly journals Development of Lipid–Polymer Hybrid Nanoparticles for Improving Oral Absorption of Enoxaparin

Pharmaceutics ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 607
Author(s):  
Bo Tang ◽  
Yu Qian ◽  
Guihua Fang
Keyword(s):  
Oral Delivery ◽  
Encapsulation Efficiency ◽  
Oral Absorption ◽  
Poloxamer 407 ◽  
Hybrid Nanoparticles ◽  
Polymer Hybrid ◽  
Study Results ◽  
Confocal Scanning

Enoxaparin, an anticoagulant that helps prevent the formation of blood clots, is administered parenterally. Here, we report the development and evaluation of lipid–polymer hybrid nanoparticles (LPHNs) for the oral delivery of enoxaparin. The polymer poloxamer 407 (P407) was incorporated into lipid nanoparticles to form gel cores and ensure high encapsulation efficiency and the controlled release of enoxaparin. In vitro results indicated that 30% of P407 incorporation offered higher encapsulation efficiency and sustained the release of enoxaparin. Laser confocal scanning microscopy (LCSM) images showed that LPHNs could not only significantly improve the accumulation of enoxaparin in intestinal villi but also facilitate enoxaparin transport into the underlayer of intestinal epithelial cells. In vivo pharmacokinetic study results indicated that the oral bioavailability of enoxaparin was markedly increased about 6.8-fold by LPHNs. In addition, its therapeutic efficacy against pulmonary thromboembolism was improved 2.99-fold by LPHNs. Moreover, LPHNs exhibited excellent biocompatibility in the intestine. Overall, the LPHN is a promising delivery carrier to boost the oral absorption of enoxaparin.

Oral delivery of liraglutide-loaded Poly-N-(2-hydroxypropyl) methacrylamide/chitosan nanoparticles: Preparation, characterization, and pharmacokinetics

2020 ◽  
pp. 088532822094788
Author(s):  
Yanan Shi ◽  
Miaomiao Yin ◽  
Yina Song ◽  
Tengteng Wang ◽  
Shiqi Guo ◽  
...  
Keyword(s):  
Oral Delivery ◽  
Oral Absorption ◽  
Chitosan Nanoparticles ◽  
Relative Bioavailability ◽  
Oral Route ◽  
Significant Challenge ◽  
Imaging Results ◽  
Hydroxypropyl Methacrylamide ◽  
Carrier Materials

The delivery of peptides or protein drugs via the oral route has always presented a significant challenge. Here, nanoparticles for the oral delivery of liraglutide are prepared. The nanoparticles are composed of the biodegradable carrier materials chitosan and poly-N-(2-hydroxypropyl) methacrylamide (pHPMA). In addition, CSKSSDYQC (CSK) and hemagglutinin-2 (HA2) are introduced into the particles to improve the in vivo bioavailability of liraglutide. The size of the nanoparticles is less than 200 nm, and the encapsulation efficiency is approximately 80%. Compared with the subcutaneously injected liraglutide solution group (100%), the relative bioavailability of the nanoparticle group modified with CSK and HA2 reached 10.12%, which is 2.53 times that of the oral liraglutide solution group. In vivo imaging results showed that pHPMA/HA2-CSK chitosan nanoparticles (pHPMA/HA-CCNPs) are retained in the gastrointestinal tract for up to 12 h, which is beneficial for oral absorption. CSK and HA2 modified pHPMA/chitosan nanoparticles significantly improved liraglutide oral bioavailability and therefore have the potential to be applied for oral administration of peptides and proteins.

Lipid Nanocarriers for Oral Delivery of Serenoa repens CO2 Extract: A Study of Microemulsion and Self-Microemulsifying Drug Delivery Systems

Planta Medica ◽  
2018 ◽  
Vol 84 (09/10) ◽  
pp. 736-742 ◽  
Author(s):  
Clizia Guccione ◽  
Maria Bergonzi ◽  
Khaled Awada ◽  
Vieri Piazzini ◽  
Anna Bilia
Keyword(s):  
Drug Delivery ◽  
Oral Delivery ◽  
Drug Delivery Systems ◽  
Oral Absorption ◽  
Delivery Systems ◽  
Array Detector ◽  
Serenoa Repens ◽  
Lipid Nanocarriers

AbstractThe aim of this study was the development and characterization of lipid nanocarriers using food grade components for oral delivery of Serenoa repens CO2 extract, namely microemulsions (MEs) and self-microemulsifying drug delivery systems (SMEDDSs) to improve the oral absorption. A commercial blend (CB) containing 320 of S. repens CO2 extract plus the aqueous soluble extracts of nettle root and pineapple stem was formulated in two MEs and two SMEDDSs. The optimized ME loaded with the CB (CBM2) had a very low content of water (only 17.3%). The drug delivery systems were characterized by dynamic light scattering, transmission electron microscopy, and high-performance liquid chromatography (HPLC) with a diode-array detector analyses in order to evaluate the size, the homogeneity, the morphology, and the encapsulation efficiency. β-carotene was selected as marker for the quantitative HPLC analysis. Additionally, physical and chemical stabilities were acceptable during 3 wk at 4 °C. Stability of these nanocarriers in simulated stomach and intestinal conditions was proved. Finally, the improvement of oral absorption of S. repens was studied in vitro using parallel artificial membrane permeability assay. An enhancement of oral permeation was found in both CBM2 and CBS2 nanoformulations comparing with the CB and S. repens CO2 extract. The best performance was obtained by the CBM2 nanoformulation (~ 17%) predicting a 30 – 70% passive oral human absorption in vivo.

scholarly journals Improving the ameliorative effects of berberine and curcumin combination via dextran-coated bilosomes on non-alcohol fatty liver disease in mice

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yi Chen ◽  
Zhaohui Jiang ◽  
Jinzhuan Xu ◽  
Jiyuan Zhang ◽  
Runbin Sun ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Oral Delivery ◽  
Fatty Liver Disease ◽  
Oral Absorption ◽  
Synergistic Effects ◽  
Drug Combinations ◽  
Promising Strategy ◽  
Anti Inflammation

Abstract Background The combination of berberine (BER) and curcumin (CUR) has been verified with ameliorative effects on non-alcohol fatty liver disease (NAFLD). However, discrepant bioavailability and biodistribution of BER and CUR remained an obstacle to achieve synergistic effects. Multilayer nanovesicles have great potential for the protection and oral delivery of drug combinations. Therein lies bile salts inserted liposomes, named as bilosomes, that possesses long residence time in the gastrointestinal tract (GIT) and permeability across the small intestine. Diethylaminoethyl dextran (DEAE-DEX) is generally used as an outside layer on the nanovesicles to increase the mucinous stability and promote oral absorption. Herein, we developed a DEAE-DEX-coated bilosome with BER and CUR encapsulated (DEAE-DEX@LSDBC) for the treatment of NAFLD. Results DEAE-DEX@LSDBC with 150 nm size exhibited enhanced permeation across mucus and Caco-2 monolayer. In vivo pharmacokinetics study demonstrated that DEAE-DEX@LSDBC profoundly prolonged the circulation time and improved the oral absorption of both BER and CUR. Intriguingly, synchronized biodistribution of BER and CUR and highest biodistribution at liver was achieved by DEAE-DEX@LSDBC, which contributed to the optimal ameliorative effects on NAFLD. It was further verified to be mainly mediated by anti-oxidation and anti-inflammation related pathways Conclusion DEAE-DEX coated bilosome displayed promoted oral absorption, prolonged circulation and synchronized biodistribution of BER and CUR, leading to improved ameliorative effects on NAFLD in mice, which provided a promising strategy for oral administration of drug combinations. Graphic abstract

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