Identification of structure–activity relationships for adverse effects of pharmaceuticals in humans. Part A: Use of FDA post-market reports to create a database of hepatobiliary and urinary tract toxicities

Ursem, Carling; Kruhlak, Naomi L.; Contrera, Joseph F.; MacLaughlin, Philip; Benz, R.; Matthews, Edwin J.

doi:10.1016/j.yrtph.2008.12.009

Cited by 49 publications

(33 citation statements)

References 18 publications

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“…This type of in silico analysis has been described previously to show that cyclobenzaprine had serotonergic properties that were then confirmed by receptor in vitro binding studies [61]. QSAR analyses have been developed to predict hepatotoxicity [62]. Similarly, FDA-approved drugs have been searched to identify previously unknown drug target interactions that were confirmed by in vivo testing [63].…”

Section: Results: Disproportionate Molecular Targets Identified By Damentioning

confidence: 95%

Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome

Burkhart

Abernethy

Jackson³

2015

J. Med. Toxicol.

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Drug features that are associated with StevensJohnson syndrome (SJS) have not been fully characterized. A molecular target analysis of the drugs associated with SJS in the FDA Adverse Event Reporting System (FAERS) may contribute to mechanistic insights into SJS pathophysiology. The publicly available version of FAERS was analyzed to identify disproportionality among the molecular targets, metabolizing enzymes, and transporters for drugs associated with SJS. The FAERS in-house version was also analyzed for an internal comparison of the drugs most highly associated with SJS. Cyclooxygenases 1 and 2, carbonic anhydrase 2, and sodium channel 2 alpha were identified as disproportionately associated with SJS. Cytochrome P450 (CYPs) 3A4 and 2C9 are disproportionately represented as metabolizing enzymes of the drugs associated with SJS adverse event reports. Multidrug resistance protein 1 (MRP-1), organic anion transporter 1 (OAT1), and PEPT2 were also identified and are highly associated with the transport of these drugs. A detailed review of the molecular targets identifies important roles for these targets in immune response. The association with CYP metabolizing enzymes suggests that reactive metabolites and oxidative stress may have a contributory role. Drug transporters may enhance intracellular tissue concentrations and also have vital physiologic roles that impact keratinocyte proliferation and survival. Data mining FAERS may be used to hypothesize mechanisms for adverse drug events by identifying molecular targets that are highly associated with druginduced adverse events. The information gained may contribute to systems biology disease models.

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Section: Results: Disproportionate Molecular Targets Identified By Damentioning

confidence: 95%

Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome

Burkhart

Abernethy

Jackson³

2015

J. Med. Toxicol.

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“…The training set comprised approximately 1600 pharmaceuticals based on observations made in humans in pharmaceutical clinical trials and/or post-market surveillance by the FDA (Ursem et al 2009). For model construction, the toxicities of the training set drugs (continuous values) were classified either as being of low risk (0, negative) or as high risk (1, positive) by identification of an optimised breakpoint activity value (BP) distinguishing active from inactive drugs.…”

Section: Hepatic and Urinary Tract Toxicitiesmentioning

confidence: 99%

Applicability of QSAR analysis to the evaluation of the toxicological relevance of metabolites and degradates of pesticide active substances for dietary risk assessment

2010

EFSA Supporting Publications

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“…In this section, we will focus on applicable methods in assessing drug renal toxicity and discuss advantages and disadvantages of each method. In silico methods have also been applied to nephrotoxicity studies (Wolfgang and Johnson, 2002;Ursem et al, 2009) and some structural alerts are known such as aristolochic acids (Fang et al, 2011), ochratoxin A (Sieber et al, 2009) or the diterpen triptolide (Xia et al, 2009 …”

Section: Part C: Methods For Nephrotoxicity Assessmentmentioning

confidence: 99%

Review of current and “omics” methods for assessing the toxicity (genotoxicity, teratogenicity and nephrotoxicity) of herbal medicines and mushrooms

Ouédraogo

Baudoux

Stévigny

et al. 2012

Journal of Ethnopharmacology

124

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Identification of structure–activity relationships for adverse effects of pharmaceuticals in humans. Part A: Use of FDA post-market reports to create a database of hepatobiliary and urinary tract toxicities

Cited by 49 publications

References 18 publications

Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome

Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome

Applicability of QSAR analysis to the evaluation of the toxicological relevance of metabolites and degradates of pesticide active substances for dietary risk assessment

Review of current and “omics” methods for assessing the toxicity (genotoxicity, teratogenicity and nephrotoxicity) of herbal medicines and mushrooms

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