Implications of Off-Target Serotoninergic Drug Activity – An Analysis of Serotonin Syndrome Reports using a Systematic Bioinformatics Approach.
STUDY OBJECTIVE: Serotonergic adverse drug events (ADEs) are caused by enhanced intra-synaptic concentrations of 5-hydroxytryptamine (5-HT). No systematic process currently exists for evaluating cumulative 5-HT and off-target toxicity of serotonergic drugs. The primary study aim was to create a Serotonergic Expanded Bioactivity Matrix (SEBM) employing a molecular bioinformatics, poly-pharmacologic approach for assessing the participation of individual 5-HT drugs in serotonin syndrome (SS) reports.
DATA SOURCES: Publicly available databases including the Food and Drug Association (FDA) Adverse Event Reporting System (FAERS), ChEMBL, DrugBank, PubChem, and Kyoto Encyclopedia of Genes and Genomes (KEGG) were queried for computational and pharmacologic data.
DESIGN: An in-house bioinformatics TargetSearch program was used to characterize 71 serotonergic drugs interacting at 13 serotonin receptor subtypes, and serotonin re-uptake transporter protein (SERT). Additionally, off-target interactions at norepinephrine transporter (NET), monoamine oxidase (MAO), and muscarinic receptors were included to define 7 poly-pharmacologic drug cohorts. Serotonin syndrome reports for each serotonergic drug were extracted from FAERS using Sternbach's and Hunter's criteria.
MEASUREMENTS AND MAIN RESULTS: A proportional reporting adverse drug reaction (ADR) ratio (PRR) was calculated from each drug's total ADEs and SS case reports and aggregated by drug bioactivity cohorts. Triple receptor interactions had a disproportionately higher number of SS cases using both Hunter's criteria (mean PRR 1.72; 95% C.I. 1.05 to 2.39) and Sternbach's (mean PRR 1.54, 95% C.I. 1.29 to 1.79). 5-Hydroxtryptamine agonists were associated with a significantly lower proportion of SS cases using Hunter's and Sternbach's criteria, respectively (mean PRR 0.49, 95% C.I. 0.17 to 0.81 and mean PRR 0.49, 95% C.I. 0.15 to 0.83). Drugs with disproportionately higher participation in SS vary considerably between the 2 diagnostic criteria.
CONCLUSION: The SEBM model suggests a possible poly-pharmacologic role in SS. Although further research is needed, off-target receptor activity may help explain differences in severity of toxicity and clinical presentation. This article is protected by copyright. All rights reserved.
|投稿者||Culbertson, Vaughn L; Rahman, Shaikh Emdadur; Bosen, Grayson C; Caylor, Matthew L; Echevarria, Megan M; Xu, Dong|
|組織名||Department of Pharmacy Practice, College of Pharmacy, Kasiska Division of Health;Sciences, Idaho State University, 1311 Central Drive, Meridian, Idaho, 83642.;Department of Biomedical & Pharmaceutical Sciences, College of Pharmacy, Kasiska;Division of Health Sciences, Idaho State University, 1311 Central Drive,;Meridian, Idaho, 83642.;College of Pharmacy, Kasiska Division of Health Sciences, Idaho State University,;1311 Central Drive, Meridian, Idaho, 83642.|