Abstract
Adverse drug reactions (ADRs) are responsible for drug candidate failure during clinical trials. It is crucial to investigate biological pathways contributing to ADRs. Here, we applied a large-scale analysis to identify overrepresented ADR-pathway combinations through merging clinical phenotypic data, biological pathway data, and drug-target relations. Evaluation was performed by scientific literature review and defining a pathway-based ADR-ADR similarity measure. The results showed that our method is efficient for finding the associations between ADRs and pathways. To more systematically understand the mechanisms of ADRs, we constructed an ADR-pathway network and an ADR-ADR network. Through network analysis on biology and pharmacology, it was found that frequent ADRs were associated with more pathways than infrequent and rare ADRs. Moreover, environmental information processing pathways contributed most to the observed ADRs. Integrating the system organ class of ADRs, we found that most classes tended to interact with other classes instead of themselves. ADR classes were distributed promiscuously in all the ADR cliques. These results reflected that drug perturbation to a certain pathway can cause changes in multiple organs, rather than in one specific organ. Our work not only provides a global view of the associations between ADRs and pathways, but also is helpful to understand the mechanisms of ADRs.
Highlights
Adverse drug reactions (ADRs) are undesired phenotypic effects that occur in human organisms after medicine administration
An ADR was associated with a pathway, when the drugs causing the ADR significantly overlapped with the drugs that affected the pathway (P ≤ 0.01) and when the number of common drugs that were shared by the ADR and the pathway was more than 10
We evaluated the performance of the method by using a textmining tool to obtain cooccurring pathway terms with ADRs and defining a pathway-based ADR-ADR similarity measure
Summary
Adverse drug reactions (ADRs) are undesired phenotypic effects that occur in human organisms after medicine administration. ADRs affect quality of life for patients, and have become a major cause of death. ADRs concern the economical profit of the pharmaceutical industries. ADRs are responsible for drug candidates’ failure to gain FDA approvals during clinical trials. Many marketed drugs have been withdrawn due to severe ADRs. For example, Cerivastatin was withdrawn from the world market, because this drug caused 52 deaths that were attributed to rhabdomyolysis and kidney failure [1]. The recognition of ADRs during the early phases of drug discovery is valuable for drug development and safety [2]
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