scholarly journals A Novel In Vitro Approach for Simultaneous Evaluation of CYP3A4 Inhibition and Kinetic Aqueous Solubility

2014 ◽  
Vol 20 (2) ◽  
pp. 254-264 ◽  
Author(s):  
José Pérez ◽  
Caridad Díaz ◽  
Francisco Asensio ◽  
Alexandra Palafox ◽  
Olga Genilloud ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Physicochemical Properties ◽  
Safety Concern ◽  
Aqueous Solubility ◽  
Cyp3a4 Inhibition ◽  
Use Of Resources ◽  
Simultaneous Evaluation ◽  
New Chemical Entities ◽  
Further Development

In the early stages of the drug discovery process, evaluation of the drug metabolism and physicochemical properties of new chemical entities is crucial to prioritize those candidates displaying a better profile for further development. In terms of metabolism, drug–drug interactions mediated through CYP450 inhibition are a significant safety concern, and therefore the effect of new candidate drugs on CYP450 activity should be screened early. In the initial stages of drug discovery, when physicochemical properties such as aqueous solubility have not been optimized yet, there might be a large number of candidate compounds showing artificially low CYP450 inhibition, and consequently potential drug–drug interaction toxicity might be overlooked. In this work, we present a novel in vitro approach for simultaneous evaluation of CYP3A4 inhibition potential and kinetic aqueous solubility (NIVA-CYPI-KS). This new methodology is based on fluorogenic CYP450 activities and turbidimetric measurements for compound solubility, and it provides a significant improvement in the use of resources and a better understanding of CYP450 inhibition data.

scholarly journals The evolution of strategies to minimise the risk of human drug-induced liver injury (DILI) in drug discovery and development

2020 ◽  
Vol 94 (8) ◽  
pp. 2559-2585 ◽  
Author(s):  
Paul A. Walker ◽  
Stephanie Ryder ◽  
Andrea Lavado ◽  
Clive Dilworth ◽  
Robert J. Riley
Keyword(s):  
Drug Discovery ◽  
Liver Injury ◽  
Drug Uptake ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
New Chemical Entities ◽  
Preclinical Animal Models ◽  
Uptake Transporters

Abstract Early identification of toxicity associated with new chemical entities (NCEs) is critical in preventing late-stage drug development attrition. Liver injury remains a leading cause of drug failures in clinical trials and post-approval withdrawals reflecting the poor translation between traditional preclinical animal models and human clinical outcomes. For this reason, preclinical strategies have evolved over recent years to incorporate more sophisticated human in vitro cell-based models with multi-parametric endpoints. This review aims to highlight the evolution of the strategies adopted to improve human hepatotoxicity prediction in drug discovery and compares/contrasts these with recent activities in our lab. The key role of human exposure and hepatic drug uptake transporters (e.g. OATPs, OAT2) is also elaborated.

scholarly journals Evaluation of Fluorescence- and Mass Spectrometry—Based CYP Inhibition Assays for Use in Drug Discovery

2008 ◽  
Vol 13 (5) ◽  
pp. 343-353 ◽  
Author(s):  
Leslie Bell ◽  
Shari Bickford ◽  
Phong Hung Nguyen ◽  
Jianling Wang ◽  
Timothy He ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Gold Standard ◽  
Low Cost ◽  
Liver Microsomes ◽  
Standard Approach ◽  
New Chemical Entities ◽  
Cyp Inhibition ◽  
Inhibitory Potential ◽  
The Impact

The potential for metabolism-related drug-drug interactions by new chemical entities is assessed by monitoring the impact of these compounds on cytochrome P450 (CYP) activity using well-characterized CYP substrates. The conventional gold standard approach for in vitro evaluation of CYP inhibitory potential uses pooled human liver microsomes (HLM) in conjunction with prototypical drug substrates, often quantified by LC-MS/MS. However, fluorescent CYP inhibition assays, which use recombinantly expressed CYPs and fluorogenic probe substrates, have been employed in early drug discovery to provide low-cost, high-throughput assessment of new chemical entities. Despite its greatly enhanced throughput, this approach has been met with mixed success in predicting the data obtained with the conventional gold standard approach (HLM+LC-MS). The authors find that the predictivity of fluorogenic assays for the major CYP isoforms 3A4 and 2D6 may depend on the quality of the test compounds. Although the structurally more optimized marketed drugs yielded acceptable correlations between the fluorogenic and HLM+LC-MS/MS assays for CYPs 3A4, 2D6, and 2C9 ( r 2 = 0.5-0.7; p < 0.005), preoptimization, early discovery compounds yielded poorer correlations ( r 2 ≤ 0.2) for 2 of these major isoforms, CYPs 3A4 and 2D6. Potential reasons for the observed differences are discussed. ( Journal of Biomolecular Screening 2008;343-353)

ECVAM and Pharmaceuticals

2002 ◽  
Vol 30 (2_suppl) ◽  
pp. 221-223 ◽  
Author(s):  
Philippe Vanparys
Keyword(s):  
Pharmaceutical Industry ◽  
Drug Development ◽  
Toxicity Tests ◽  
Development Phase ◽  
Use Of Resources ◽  
Discovery Phase ◽  
Test Models ◽  
New Chemical Entities ◽  
Phase Medium

In the pharmaceutical industry, toxicology testing is normally done by preclinical scientists during the Development phase. In the last decade, the implementation of high-throughput screens during the Discovery phase has resulted in an ever-increasing number of lead candidates to be selected for drug development. The low throughput of the conventional safety tests is a bottleneck in the drug-development process. The pharmaceutical industry needs new techniques, down-scaled tests and in vitro alternative test models to determine the absorption, distribution, metabolism, and excretion (ADME) and toxicology profiles of compounds in the late-Discovery phase and/or early in the Development phase. Medium-throughput ADME and toxicity tests will enhance the selection of safer new chemical entities for animals and/or humans. Consequently, this testing strategy will not only reduce the use of resources and the overall development time, but will also result in a substantial decrease in animal use.

scholarly journals Cannabinoid glycosides: In vitro production of a new class of cannabinoids with improved physicochemical properties

2017 ◽  
Author(s):  
Janee’ M. Hardman ◽  
Robert T. Brooke ◽  
Brandon J. Zipp
Keyword(s):  
Physicochemical Properties ◽  
Targeted Delivery ◽  
Treatment Options ◽  
Stevia Rebaudiana ◽  
Aqueous Solubility ◽  
In Vitro Production ◽  
New Class ◽  
Delivery Options ◽  
Arachidonoyl Glycerol

AbstractThe cannabinoid signaling system has recently garnered attention as a therapeutic target for numerous indications, and cannabinoids are now being pursued as new treatment options in diverse medical fields such as neurology, gastroenterology, pain management, and oncology. Cannabinoids are extremely hydrophobic and relatively unstable compounds, and as a result, formulation and delivery options are severely limited. Enzymatic glycosylation is a strategy to alter the physicochemical properties of small molecules, often improving their stability and aqueous solubility, as well as enabling site-specific drug targeting strategies. To determine if cannabinoids are a candidate for glycosylation, a library of glucosyltransferase (UGT) enzymes was screened for glycosylation activity towards various cannabinoids. The UGT76G1 enzyme from Stevia rebaudiana has been identified as having glucosyltransferase activity towards a broad range of cannabinoids. Compounds that were successfully glycosylated by UGT76G1 include the phytocannabinoids cannabidiol (CBD), Δ9-tetrahydrocannabinol (Δ9-THC), cannabidivarin (CBDV), and cannabinol (CBN), and the human endocannabinoids anandamide (AEA), 2-arachidonoyl-glycerol (2AG), 1-arachidonoyl-glycerol (1AG), and synaptamide (DHEA). Interestingly, UGT76G1 is able to transfer primary, secondary, and tertiary glycosylations at each acceptor of most of the cannabinoids tested. Additionally, Os03g0702000p, a glycosyltransferase from Oryza sativa, was able to transfer secondary glucose residues onto cannabinoid monoglycosides previously established by UGT76G1. This new class of cannabinoid-glycosides has been termed cannabosides. The compounds have greatly improved solubility in aqueous solutions. This increased aqueous solubility may enable new oral pharmaceutical delivery options for cannabinoids, as well as targeted delivery and release of cannabinoids within the intestines through glycoside prodrug metabolism.

scholarly journals Synthesis and Antiviral Activity of Novel 1,3,4-Thiadiazole Inhibitors of DDX3X

Molecules ◽  
2019 ◽  
Vol 24 (21) ◽  
pp. 3988 ◽  
Author(s):  
Brai ◽  
Ronzini ◽  
Riva ◽  
Botta ◽  
Zamperini ◽  
...  
Keyword(s):  
Aqueous Solubility ◽  
Biological Profile ◽  
New Family ◽  
Dead Box ◽  
Starting Point ◽  
Pharmacokinetic Properties ◽  
Good Starting Point ◽  
Further Development ◽  
Micromolar Range

The human ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3X) emerged as a novel therapeutic target in the fight against both infectious diseases and cancer. Herein, a new family of DDX3X inhibitors was designed, synthesized, and tested for its inhibitory action on the ATPase activity of the enzyme. The potential use of the most promising derivatives it has been investigated by evaluating their anti-HIV-1 effects, revealing inhibitory activities in the low micromolar range. A preliminary ADME analysis demonstrated high metabolic stability and good aqueous solubility. The promising biological profile, together with the suitable in vitro pharmacokinetic properties, make these novel compounds a very good starting point for further development.

scholarly journals In vitro/in vivo performance of different complexes of itraconazole used in the treatment of vaginal candidiasis

2012 ◽  
Vol 48 (4) ◽  
pp. 759-772 ◽  
Author(s):  
Mohammad Aamir Mirza ◽  
Mohammad Akhlaquer Rahman ◽  
Sushama Talegaonkar ◽  
Zeenat Iqbal
Keyword(s):  
Fulvic Acid ◽  
Aqueous Solubility ◽  
Water Soluble ◽  
Vaginal Candidiasis ◽  
Scanning Calorimetry ◽  
Drug Molecules ◽  
Water Soluble Drug ◽  
New Chemical Entities

A large majority of new chemical entities and many existing drug molecules exhibit poor aqueous solubility, which may limit their potential use in developing drug formulations, with optimum bioavailability. One of the approaches to improve the solubility of a poorly water soluble drug and eventually its bioavailability is complexation with agents like humic acid (HA), fulvic acid (FA), β-cyclodextrin (β-CD), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and caffeine (Caff). The current work emphasized at employing these agents to prepare different complexes and their in vitro/in vivo assessment. All the complexes evaluated for their complexation efficiency and authenticated by molecular modeling; conformational analysis, differential scanning calorimetry (DSC), X-ray diffraction (XRD), nuclear magnetic resonance (NMR) and mass spectroscopy. Furthermore, the complexes were assessed in an in vivo, rat vaginal model for their efficacy in treatment of vaginal candidiasis. Amongst the five tested complexes, fulvic acid-itraconazole complex yielded better solubility as well as in vivo efficacy and therefore may further be explored for developing a commercial formulation for treating vaginal candidiasis.

PREPARATION AND CHARACTERISATION OF ACETYLATED WHEAT STARCH SUPPORTING FOR DIABETES TREATMENT

2018 ◽  
Vol 8 (5) ◽  
pp. 78-84
Author(s):  
Uyen Tran Thi Ngoc ◽  
Nam Nguyen Khac ◽  
Dung Tran Huu
Keyword(s):  
Physicochemical Properties ◽  
Resistant Starch ◽  
Starch Content ◽  
Degree Of Substitution ◽  
Wheat Starch ◽  
Diabetes Treatment ◽  
Glucose Response ◽  
Swelling Capacity ◽  
Wheat Starches

Background: The purpose of the study was to prepare acetylated wheat starches which have amylase hydrolysis resistant capacity to use as functional food supporting for diabetes treatment. Method: Acetate wheat starches were prepared by acetylation reaction of native wheat starch with different mole ratios of acetic anhydride. These starches were determined for the physicochemical properties by 1H-NMR, SEM, X-ray, DSC, solubility and swelling capacity, the resistant capacity by amylase hydrolysis in-vitro. Results: Acetate wheat starches were prepared successfully with the increase in acetyl content and degree of substitution corresponding with the increase of anhydride acetic, which resulted in the change of physicochemical properties of the wheat starches, including constitution, solubility, swelling capacity and contributed to the increase in resistant starch content in the acetate wheat starches. The AC150-9 containing 2.42% acetyl with degree of substitution 0,094 and resistant starch 32,11% is acceptable by FDA guideline about food safety. Conclusion: Acetate wheat starches contain low rate of digestive starch, while containing a higher proportion of resistant starch than natural wheat starch, possessing a high resistance to amylase activities. Thus, it is hope that this kind of starch to control the rapid increase of postprandual blood glucose response for diabetes treatments effectively. Key words: Acetate wheat starch, substitution, DS, RS, amylase

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