<i>In vitro</i>cell-based models of drug-induced hepatotoxicity screening: progress and limitation

Mirahmad, Maryam; Sabourian, Reyhaneh; Mahdavi, Mohammad; Larijani, Bagher; Safavi, Mohammadreza

doi:10.1080/03602532.2022.2064487

Cited by 10 publications

(11 citation statements)

References 195 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although cell-based models are valuable tools for studying the BBB, they have some limitations. For instance, they lack fluid shear stress and other components of the BBB, which can result in inaccurate estimations of drug transport [ 140 ].…”

Section: Various Models To Study Bbbmentioning

confidence: 99%

Nanomaterials as drug delivery agents for overcoming the blood-brain barrier: A comprehensive review

Kulkarni,

Patel,

Patel

et al. 2023

ADMET DMPK

View full text Add to dashboard Cite

Background and Purpose: The blood-brain barrier (BBB), a critical interface of specialized endothelial cells, plays a pivotal role in regulating molecular and ion transport between the central nervous system (CNS) and systemic circulation. Experimental Approach: This review aims to delve into the intricate architecture and functions of the BBB while addressing challenges associated with delivering therapeutics to the brain. Historical milestones and contemporary insights underscore the BBB's significance in protecting the CNS. Key Results: Innovative approaches for enhanced drug transport include intranasal delivery exploiting olfactory and trigeminal pathways, as well as techniques like temporary BBB opening through chemicals, receptors, or focused ultrasound. These avenues hold the potential to reshape conventional drug delivery paradigms and address the limitations posed by the BBB's selectivity. Conclusion: This review underscores the vital role of the BBB in maintaining CNS health and emphasizes the importance of effective drug delivery through this barrier. Nanoparticles emerge as promising candidates to overcome BBB limitations and potentially revolutionize the treatment of CNS disorders. As research progresses, the application of nanomaterials shows immense potential for advancing neurological therapeutics, albeit with careful consideration of safety aspects.

show abstract

Section: Various Models To Study Bbbmentioning

confidence: 99%

Nanomaterials as drug delivery agents for overcoming the blood-brain barrier: A comprehensive review

Kulkarni,

Patel,

Patel

et al. 2023

ADMET DMPK

View full text Add to dashboard Cite

show abstract

“…Additionally, improved standardization and cost reduction of metabolically more competent cells (e.g. HepaRG or hiPSCs) would allow to expand their implementation in HT systems (Mirahmad et al 2022).…”

Section: Moa Speci C Metabolite Pro Lesmentioning

confidence: 99%

“…Drug-induced liver injury (DILI) represents the leading cause of failure in new pharmaceutical development and post approval compound withdrawals (Onakpoya et al 2016). Therefore, hepatotoxicity is of primary concern in compound development and considerable efforts have been directed to the development of assays to evaluate liver toxicity (Mirahmad et al 2022). Several liver cell lines have been successfully used for in vitro metabolomics to identify modes of action of liver toxicity ).…”

Section: Introductionmentioning

confidence: 99%

High Throughput Metabolomics In vitro Platform for The Identification of Hepatotoxicity Modes of Action

Ramirez-Hincapie

Birk

Ternes³

et al. 2022

Preprint

View full text Add to dashboard Cite

Cell-based metabolomics provides multiparametric physiologically relevant readouts that can be highly advantageous for improved, biologically based decision making in early stages of compound development. Here we present the development of a 96-well plate LC-MS-based targeted metabolomics screening platform for the classification of liver toxicity MoAs in HepG2 cells. Different parameters of the workflow (cell seeding density, passage number, cytotoxicity testing, sample preparation, metabolite extraction, analytical method, and data processing) were optimized and standardized to increase the efficiency of the testing platform. The applicability of the system was tested with seven substances known to be representative of three different liver toxicity MoAs (peroxisome proliferation, liver enzyme induction and liver enzyme inhibition). Multivariate and univariate analyses showed a dose response of the metabolic effects, a clear differentiation between liver toxicity MoAs and resulted in the identification of metabolite patterns specific for each MoA. Key metabolites indicative of both, general and mechanistic specific hepatotoxicity were identified. The method presented here offers a multiparametric, mechanistic-based and cost-effective hepatotoxicity screening that provides MoA classification and sheds light into the pathways involved in the toxicological mechanism. This assay can be implemented as a reliable compound screening platform for improved safety assessment in early compound development pipelines.

show abstract

Section: Introductionmentioning

confidence: 99%

“…In general, drug metabolism gone wrong and giving rise to dangerous levels of reactive metabolites (RMs) continues to require considerable attention in the drug design process, as highlighted in recent reviews focusing on medicinal chemistry 1−4 and on early detection of biological signals. 5,6 It is generally accepted that putting a methyl on benzene to give toluene moderates its toxicity, especially its carcinogenecity. 7 In drug design it is also common to put a methyl on an aromatic to provide a handle for directed drug metabolism ("soft site") and, in particular, for modifying other key properties.…”

Section: Introductionmentioning

confidence: 99%

Non-innocuous Consequences of Metabolic Oxidation of Alkyls on Arenes

Claesson¹,

Parkes²

2022

J. Med. Chem.

View full text Add to dashboard Cite

Reactive metabolite (RM) formation is widely accepted as playing a pivotal role in causing adverse idiosyncratic drug reactions, with most attention paid to drug-induced liver injury. Mechanisms of RM formation are determined by the drug’s properties in relation to human enzymes transforming the drug. This Perspective focuses on enzymatic oxidation of alkyl groups on aromatics leading to quinone methides and benzylic alcohol sulfates as RMs, a topic that has not received very much attention. Unlike previous overviews, we will include in our Perspective several fulvene-like methides such as 3-methyleneindole. We also speculate that a few older drugs may form non-reported methides of this class. In addition, we report a few guiding DFT calculations of changes in free energy on going from a benzylic alcohol to the corresponding methide. Particularly facile reactions of 2-aminothiazole-5-methanol and 4-aminobenzyl alcohol are noted.

show abstract

In vitrocell-based models of drug-induced hepatotoxicity screening: progress and limitation

Cited by 10 publications

References 195 publications

Nanomaterials as drug delivery agents for overcoming the blood-brain barrier: A comprehensive review

Nanomaterials as drug delivery agents for overcoming the blood-brain barrier: A comprehensive review

High Throughput Metabolomics In vitro Platform for The Identification of Hepatotoxicity Modes of Action

Non-innocuous Consequences of Metabolic Oxidation of Alkyls on Arenes

Contact Info

Product

Resources

About