scholarly journals In Vitro, In Silico, and In Vivo Assessments of Pharmacokinetic Properties of ZM241385

Molecules ◽  
2020 ◽  
Vol 25 (5) ◽  
pp. 1106 ◽  
Author(s):  
Jin-Ju Byeon ◽  
Min-Ho Park ◽  
Seok-Ho Shin ◽  
Yuri Park ◽  
Byeong ill Lee ◽  
...  
Keyword(s):  
In Silico ◽  
Hepatic Clearance ◽  
Brain Regions ◽  
Rat Plasma ◽  
Pbpk Modeling ◽  
Pharmacokinetic Properties ◽  
Low Exposure

Parkinson’s disease is one of the most common neurodegenerative diseases. Adenosine regulates the response to other neurotransmitters in the brain regions related to motor function. In the several subtypes of adenosine receptors, especially, adenosine 2A receptors (A2ARs) are involved in neurodegenerative conditions. ZM241385 is one of the selective non-xanthine A2AR antagonists with high affinity in the nanomolar range. This study describes the in vitro and in vivo pharmacokinetic properties of ZM241385 in rats. A liquid chromatography-quadrupole time-of-flight mass spectrometric (LC-qToF MS) method was developed for the determination of ZM241385 in rat plasma. In vivo IV administration studies showed that ZM241385 was rapidly eliminated in rats. However, the result of in vitro metabolic stability studies showed that ZM241385 had moderate clearance, suggesting that there is an extra clearance pathway in addition to hepatic clearance. In addition, in vivo PO administration studies demonstrated that ZM241385 had low exposure in rats. The results of semi-mass balance studies and the in silico PBPK modeling studies suggested that the low bioavailability of ZM241385 after oral administration in rats was due to the metabolism and by liver, kidney, and gut.

A sensitive HPLC-FL method to simultaneously determine febuxostat and diclofenac in rat plasma: assessment of metabolic drug interactions in vitro and in vivo

2020 ◽  
Vol 12 (16) ◽  
pp. 2166-2175 ◽  
Author(s):  
Dong-Gyun Han ◽  
Kyu-Sang Kim ◽  
Seong-Wook Seo ◽  
Young Mee Baek ◽  
Yunjin Jung ◽  
...  
Keyword(s):  
Sample Preparation ◽  
Drug Interactions ◽  
Simultaneous Determination ◽  
Small Volume ◽  
Rat Plasma ◽  
Metabolic Drug ◽  
Simple Sample Preparation

We developed a sensitive, simple and validated HPLC-FL method for simultaneous determination of FEB and DIC in rat plasma. The method requires a relatively small volume of sample, has simple sample preparation and excellent sensitivity.

scholarly journals in Silico Docking and Molecular Dynamic Simulation of 3-Dehydroquinate Dehydratase from Mycobacterium Tuberculosis Through Virtual Screening and Pharmacokinetics Studies

2020 ◽  
Author(s):  
Mustafa Alhaji Isa ◽  
Muhammad M Ibrahim
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Virtual Screening ◽  
Molecular Dynamic ◽  
In Silico ◽  
Md Simulation ◽  
Binding Energies ◽  
In Silico Docking ◽  
Pharmacokinetic Properties

The 3-hydroquinate synthase (DHQase) is an enzyme that catalyzes the third step of the shikimate pathway in <i>Mycobacterium tuberculosis</i> (MTB), by converting 3-dehydroquinate into 3-dehydroshikimate. In this study, the novel inhibitors of DHQase from MTB was identified using in silico approach. The crystal structure of DHQase bound to 1,3,4-trihydroxy-5-(3-phenoxypropyl)-cyclohexane-1-carboxylic acid (CA) obtained from the Protein Data Bank (PDB ID: 3N76). The structure prepared through energy minimization and structure optimization. A total of 9699 compounds obtained from Zinc and PubChem databases capable of binding to DHQase and subjected to virtual screening through Lipinski’s rule of five and molecular docking analysis. Eight (8) compounds with good binding energies, ranged between ─8.99 to ─8.39kcal/mol were selected, better than the binding energy of ─4.93kcal/mol for CA and further filtered for pharmacokinetic properties (Absorption, Distribution, Metabolism, Excretion, and Toxicity or ADMET). Five compounds (ZINC14981770, ZINC14741224, ZINC14743698, ZINC13165465, and ZINC8442077) which had desirable pharmacokinetic properties selected for molecular dynamic (MD) simulation and molecular generalized born surface area (MM-GBSA) analyses. The results of the analyses showed that all the compounds formed stable and rigid complexes after the 50ns MD simulation and also had a lower binding as compared to CA. Therefore, these compounds considered as good inhibitors of MTB after in vitro and in vivo validation.”

Molecular Modeling Approaches for the Prediction of Selected Pharmacokinetic Properties

2019 ◽  
Vol 18 (26) ◽  
pp. 2230-2238 ◽  
Author(s):  
Emilio S. Petito ◽  
David J.R. Foster ◽  
Michael B. Ward ◽  
Matthew J. Sykes
Keyword(s):  
Molecular Modeling ◽  
In Silico ◽  
Volume Of Distribution ◽  
Future Directions ◽  
Unbound Fraction ◽  
Drug Candidates ◽  
New Methods ◽  
Pharmacokinetic Properties

Poor profiles of potential drug candidates, including pharmacokinetic properties, have been acknowledged as a significant hindrance to the development of modern therapeutics. Contemporary drug discovery and development would be incomplete without the aid of molecular modeling (in-silico) techniques, allowing the prediction of pharmacokinetic properties such as clearance, unbound fraction, volume of distribution and bioavailability. As with all models, in-silico approaches are subject to their interpretability, a trait that must be balanced with accuracy when considering the development of new methods. The best models will always require reliable data to inform them, presenting significant challenges, particularly when appropriate in-vitro or in-vivo data may be difficult or time-consuming to obtain. This article seeks to review some of the key in-silico techniques used to predict key pharmacokinetic properties and give commentary on the current and future directions of the field.

scholarly journals Gouda Cheese with Modified Content of β-Casein as a Source of Peptides with ACE- and DPP-IV-Inhibiting Bioactivity: A Study Based on In Silico and In Vitro Protocol

2021 ◽  
Vol 22 (6) ◽  
pp. 2949
Author(s):  
Anna Iwaniak ◽  
Damir Mogut ◽  
Piotr Minkiewicz ◽  
Justyna Żulewska ◽  
Małgorzata Darewicz
Keyword(s):  
In Silico ◽  
Ace Inhibition ◽  
Water Soluble ◽  
In Vivo Studies ◽  
Quantitative Parameters ◽  
Dpp Iv ◽  
Gouda Cheese

In silico and in vitro methods were used to analyze ACE- and DPP-IV-inhibiting potential of Gouda cheese with a modified content of β-casein. Firstly, the BIOPEP-UWM database was used to predict the presence of ACE and DPP-IV inhibitors in casein sequences. Then, the following Gouda cheeses were produced: with decreased, increased, and normative content of β-casein after 1 and 60 days of ripening each (six variants in total). Finally, determination of the ACE/DPP-IV-inhibitory activity and the identification of peptides in respective Gouda-derived water-soluble extracts were carried out. The identification analyses were supported with in silico calculations, i.e., heatmaps and quantitative parameters. All Gouda variants exhibited comparable ACE inhibition, whereas DPP-IV inhibition was more diversified among the samples. The samples derived from Gouda with the increased content of β-casein (both stages of ripening) had the highest DPP-IV-inhibiting potency compared to the same samples measured for ACE inhibition. Regardless of the results concerning ACE and DPP-IV inhibition among the cheese samples, the heatmap showed that the latter bioactivity was predominant in all Gouda variants, presumably because it was based on the qualitative approach (i.e., peptide presence in the sample). Our heatmap did not include the bioactivity of a single peptide as well as its quantity in the sample. In turn, the quantitative parameters showed that the best sources of ACE/DPP-IV inhibitors were all Gouda-derived extracts obtained after 60 days of the ripening. Although our protocol was efficient in showing some regularities among Gouda cheese variants, in vivo studies are recommended for more extensive investigations of this subject.

Simultaneous Determination of Six Coumarins in Rat Plasma and Metabolites Identification of Bergapten in Vitro and in Vivo

2018 ◽  
Vol 66 (18) ◽  
pp. 4602-4613 ◽  
Author(s):  
Man Liao ◽  
Gengshen Song ◽  
Xiaoye Cheng ◽  
Xinpeng Diao ◽  
Yupeng Sun ◽  
...  
Keyword(s):  
Simultaneous Determination ◽  
Rat Plasma

scholarly journals Neuropharmacokinetic visualization of regional and subregional unbound antipsychotic drug transport across the blood–brain barrier

2021 ◽  
Author(s):  
Dominika Luptáková ◽  
Theodosia Vallianatou ◽  
Anna Nilsson ◽  
Reza Shariatgorji ◽  
Margareta Hammarlund-Udenaes ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Drug Transport ◽  
Mass Spectrometry Imaging ◽  
Brain Regions ◽  
Brain Barrier ◽  
Blood Brain ◽  
Comprehensive Determination

AbstractComprehensive determination of the extent of drug transport across the region-specific blood–brain barrier (BBB) is a major challenge in preclinical studies. Multiple approaches are needed to determine the regional free (unbound) drug concentration at which a drug engages with its therapeutic target. We present an approach that merges in vivo and in vitro neuropharmacokinetic investigations with mass spectrometry imaging to quantify and visualize both the extent of unbound drug BBB transport and the post-BBB cerebral distribution of drugs at regional and subregional levels. Direct imaging of the antipsychotic drugs risperidone, clozapine, and olanzapine using this approach enabled differentiation of regional and subregional BBB transport characteristics at 20-µm resolution in small brain regions, which could not be achieved by other means. Our approach allows investigation of heterogeneity in BBB transport and presents new possibilities for molecular psychiatrists by facilitating interpretation of regional target-site exposure results and decision-making.

scholarly journals In Vitro Dissolution and in Silico Modeling Shortcuts in Bioequivalence Testing

Pharmaceutics ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 45 ◽  
Author(s):  
Moawia M. Al-Tabakha ◽  
Muaed J. Alomar
Keyword(s):  
Computer Simulation ◽  
In Silico ◽  
Immediate Release ◽  
Pbpk Modeling ◽  
In Vitro Dissolution ◽  
Formulation Development ◽  
Drug Formulations ◽  
Drug Modeling

Purpose: To review in vitro testing and simulation platforms that are in current use to predict in vivo performances of generic products as well as other situations to provide evidence for biowaiver and support drug formulations development. Methods: Pubmed and Google Scholar databases were used to review published literature over the past 10 years. The terms used were “simulation AND bioequivalence” and “modeling AND bioequivalence” in the title field of databases, followed by screening, and then reviewing. Results: A total of 22 research papers were reviewed. Computer simulation using software such as GastroPlus™, PK-Sim® and SimCyp® find applications in drug modeling. Considering the wide use of optimization for in silico predictions to fit observed data, a careful review of publications is required to validate the reliability of these platforms. For immediate release (IR) drug products belonging to the Biopharmaceutics Classification System (BCS) classes I and III, difference factor (ƒ1) and similarity factor (ƒ2) are calculated from the in vitro dissolution data of drug formulations to support biowaiver; however, this method can be more discriminatory and may not be useful for all dissolution profiles. Conclusions: Computer simulation platforms need to improve their mechanistic physiologically based pharmacokinetic (PBPK) modeling, and if prospectively validated within a small percentage of error from the observed clinical data, they can be valuable tools in bioequivalence (BE) testing and formulation development.

scholarly journals Activities ofN,N′-Diarylurea MMV665852 Analogs against Schistosoma mansoni

2015 ◽  
Vol 59 (4) ◽  
pp. 1935-1941 ◽  
Author(s):  
Noemi Cowan ◽  
Philipp Dätwyler ◽  
Beat Ernst ◽  
Chunkai Wang ◽  
Jonathan L. Vennerstrom ◽  
...  
Keyword(s):  
Physicochemical Properties ◽  
Schistosoma Mansoni ◽  
In Silico ◽  
Worm Burden ◽  
Unmet Need ◽  
Intestinal Wall ◽  
Content Type ◽  
Pharmacokinetic Properties

ABSTRACTThere is an unmet need to discover and develop novel antischistosomal drugs. As exemplified by MMV665852,N,N′-diarylureas have recently emerged as a promising antischistosomal chemotype. In this study, we evaluated the structure-activity relationships of 46 commercially available analogs of MMV665852 on newly transformed schistosomula (NTS) and adultSchistosoma mansoniwormsin vitro. Active compounds were evaluated with a cytotoxicity assay,in silicocalculations, metabolic stability studies, and anin vivoassay with mice harboring adultS. mansoniworms. Of the 46 compounds tested at 33.3 μM, 13 and 14 compounds killed NTS and adult worms, respectively, within 72 h. Nine compounds had 90% inhibitory concentrations (IC90s) of ≤10 μM against adult worms, with selectivity indexes of ≥2.8. Their physicochemical properties and permeation through an artificial membrane indicated good to moderate intestinal absorption. Their metabolic stabilities ranged from low to high. Despite satisfactoryin vitroresults andin silicopredictions, only one compound resulted in a statistically significant worm burden reduction (66%) after administration of a single oral dose of 400 mg/kg of body weight toS. mansoni-infected mice. Worm burden reductions of 0 to 43% were observed for the remaining eight compounds tested. In conclusion, several analogs of theN,N′-diarylurea MMV665852 had high efficacy againstS. mansoniin vitroand favorable physicochemical properties for permeation through the intestinal wall. To counteract the low efficacy observed in the mouse model, further investigations should focus on identifying compounds with improved solubility and pharmacokinetic properties.

Quantitative bioanalytical LC–MS/MS assay for S130 in rat plasma-application to a pharmacokinetic study

Bioanalysis ◽  
2019 ◽  
Vol 11 (16) ◽  
pp. 1469-1481 ◽  
Author(s):  
Yanping Guan ◽  
Yuanyuan Fu ◽  
Yao Liu ◽  
Siyi Wang ◽  
Man Zhao ◽  
...  
Keyword(s):  
Rat Plasma ◽  
Negative Influence ◽  
Selected Reaction Monitoring ◽  
Toxicological Evaluation ◽  
Colorectal Cancer Cells ◽  
The Us ◽  
Us Fda

Aim: An innovative Atg4B inhibitor, S130, exhibited a negative influence on colorectal cancer cells in vitro and in vivo. To assist reliable toxicodynamic and pharmacokinetic evaluation, an LC–MS/MS assay of S130 in rat plasma must be necessary. Results: An LC–MS/MS assay for determination of S130 in rat plasma has been first developed and fully verified whose values met the admissible limits as per the US FDA guidelines. Chromatographic separation was achieved by using an isocratic elution after 3 min. MS was conducted under the ESI+ mode fitted with selected reaction monitoring. The calibration curve proved acceptable linearity over 0.50–800 ng/ml. Conclusion: The developed LC–MS/MS assay of S130 in rat plasma is easily applicable in pharmacokinetics study and the further toxicological evaluation.

Sign in / Sign up

Export Citation Format

Share Document