Evidence-based absorption, distribution, metabolism, excretion (ADME) and its interplay with alternative toxicity methods

Tsaioun, Katya; Blaauboer, Bas J.; Hartung, Thomas

doi:10.14573/altex.1610101

Cited by 86 publications

(65 citation statements)

References 116 publications

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“…The implementation of ADMET profiling of drug candidates, in conjunction with biological efficacy and safety optimization, has dramatically reduced pharmacokinetic failures in clinical trials and leads to the development of effective compounds in the process of drug design 23 . ADMET properties, as derived from admetSAR server, reveal that in case of absorption, the active phytochemicals for different types of models such as BBB penetration, P-glycoprotein substrate, renal organic cation transporter, and the human intestinal absorption and CacO 2 permeability showed positive results which strongly support the ability of phytochemical to act as drug.…”

Section: Resultsmentioning

confidence: 99%

Untitled

2018

IJPSR

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Atherosclerosis is a condition where the arteries become narrowed and hardened due to an excessive build up of plaque around the artery wall. The disease disrupts the flow of blood around the body, posing serious cardiovascular complications. Liver X alpha receptor (LXRα) is highly expressed in liver, function as cholesterol sensors with important roles in regulating cholesterol homeostasis. The leaves of Corchorus trilocularis possess anti-atherosclerotic property along with its anti hyperglycemic activity. The Genetic Optimization for Ligand Docking (GOLD) software resulted in identifying the best compound that interacts with the receptor. The present study was carried out to evaluate the anti-atherosclerotic activity of the ethanolic leaf extract of Corchorus trilocularis against LXRα by using GOLD software. Phytochemical molecules were retrieved from the pubchem database and the 2D chemical structures were generated from Simplified Molecular Input Line Entry Specification (SMILES) notation by using the Chemsketch Software. 3-Dimensional structure of LXRα was retrieved using Protein Data Bank. The structure was viewed using Swiss -PDB Viewer to form a better understanding of the molecule in order to use it as a drug target. Among the twelve phytochemicals, 10-Methyl-E-11-tridecen-1-ol propionate has the GOLD score of 28.33. From the in-silico docking results, it is quite evident that phytochemicals of Corchorus trilocularis leaves have the great potential against atherosclerosis and may act as better leads and in turn prevent atherosclerosis. ADME and toxicity was predicted by using ADMET structure-activity relationship database.

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Section: Resultsmentioning

confidence: 99%

Untitled

2018

IJPSR

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“…The computational tools are still rather limited, but a genotoxic metabolite of a non-genotoxic mother compound, for example, would strongly affect TTC values in the current use. A number of reviews on metabolic prediction tools are available (Boobis et al, 2002;Kulkarni et al, 2005;Norinder and Bergström, 2006;Mostrag-Szlichtyng and Worth, 2010;Tsaioun et al, 2016 An especially interesting combination is the one of TTC with read-across or (Q)SAR, especially as both are fast and not costly. Establishing a probability of hazard using these in silico tools as discussed above can synergize with TTC ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Thresholds of Toxicological Concern – Setting a threshold for testing below which there is little concern

Hartung

2017

ALTEX

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“…Advances in the field have been recently summarized (Tsaioun et al, 2016). ADME (absorption, distribution, metabolism, elimination) has rapidly evolved over the past two decades, creating a unique interdisciplinary interface between medicinal chemists, biologists, formulators, toxicologists, clinicians, and regulators across industries, but has advanced most rapidly in the pharmaceutical industry.…”

Section: Reproduction Studiesmentioning

confidence: 99%

Rebooting the generally recognized as safe (GRAS) approach for food additive safety in the US

Hartung

2018

ALTEX

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SummaryThe US Food and Drug Administration (FDA) has premarket review authority over food additives, but a food manufacturer may, according to the legislation, intentionally add a substance to human food or animal food without their premarket review or approval if the substance is generally recognized, among qualified experts, to be safe under the conditions of its intended use. Generally recognized as safe (GRAS) implies that the current scientific community agrees on the adequacy of how data is generated. This system has come under public pressure because of doubts as to its efficiency and the FDA's recent GRAS rule is part of the response. The FDA guidance for testing food additives, known as the "Redbook", is about two decades old. Work toward a new "Redbook" is on the way, but the US Grocery Manufacturer Association (GMA) also has initiated the development of an independent standard on how to perform GRAS determinations. This review of the current guidance shows a very rigorous system for higher concern levels, but also many waiving options. Opportunities and challenges for safety evaluations of food additives are discussed. Where scientific progress has allowed improving existing and adapting new methods, these should be adopted to improve product safety and animal welfare. The continuous adaptation of such improved methods is therefore needed. Especially, there are opportunities to embrace developments within the toxicity testing for the 21 st century movement and evidence-based toxicology approaches. Also, the growing understanding of the limitations of traditional tests needs to be considered.

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Evidence-based absorption, distribution, metabolism, excretion (ADME) and its interplay with alternative toxicity methods

Cited by 86 publications

References 116 publications

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Untitled

Thresholds of Toxicological Concern – Setting a threshold for testing below which there is little concern

Rebooting the generally recognized as safe (GRAS) approach for food additive safety in the US

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