Reactive Metabolites in Early Drug Development: Predictive In vitro Tools

Author(s): Olavi Pelkonen, Markku Pasanen, Ari Tolonen, Mikko Koskinen, Jukka Hakkola, Khaled Abass, Jaana Laine, Merja Hakkinen, Risto Juvonen, Seppo Auriola, Markus Storvik, Pasi Huuskonen, Timo Rousu, Maiju Rahikkala

Journal Name: Current Medicinal Chemistry

Volume 22 , Issue 4 , 2015

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Abstract:

Drug metabolism can result in the formation of highly reactive metabolites that are known to play a role in toxicity resulting in a significant proportion of attrition during drug development and clinical use. Thus, the earlier such reactivity was detected, the better. This review summarizes our multi-year project, together with pertinent literature, to examine a battery of in vitro tests capable of detecting the formation of reactive metabolites. Principal prerequisites for such tests were delineated: chemicals known/not known to cause tissue injury and produce reactive metabolites, activation system (mainly human-derived), small- and large-molecular targets (small-molecular trappers, peptides, proteins), analytical techniques (mass spectrometry), and cellular toxicity biomarkers. The current status of in vitro tools to detect reactive intermediates is the following: 1. Small-molecular trapping agents such glutathione or cyanide detect the production of reactive species with high sensitivity by proper MS technique. However, it seems that also putative “negatives” give rise to corresponding adducts. 2. Results from peptide and dG (DNA targeting) trapper studies are generally in line with those of small-molecular trappers, although also important differences exist. These two trapping platforms do not overlap. 3. It is anticipated that the in vitro adduct studies could be fully interpreted only in conjunction with toxicity biomarker (such as the Nrf2 pathway) information from whole cells or tissues. However, while there are tools to characterize the chemical liability and there are correlation between individual/integrated endpoints and toxicity, there are still severe gaps in understanding the mechanisms behind the link between reactive metabolites and adverse effects.

Keywords: CYP, cytochrome P450, drug metabolizing enzymes, glutathione, oligonucleotide trappers, oligopeptide trappers, potassium cyanide, reactive metabolites, semicarbazide, trapping agents.

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Article Details

VOLUME: 22
ISSUE: 4
Year: 2015
Published on: 26 December, 2014
Page: [538 - 550]
Pages: 13
DOI: 10.2174/0929867321666141012175543
Price: $65

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