Dataset Information

Drug-drug-gene interactions as mediators of adverse drug reactions to diclofenac and statins: a case report and literature review.

ABSTRACT: Concomitant treatment with drugs that inhibit drug metabolising enzymes and/or transporters, such as commonly prescribed statins and nonsteroidal anti-inflammatory drugs (NSAIDs), has been associated with prolonged drug exposure and increased risk of adverse drug reactions (ADRs) due to drug-drug interactions. The risk is further increased in patients with chronic diseases/comorbidities who are more susceptible because of their genetic setup or external factors. In that light, we present a case of a 46-year-old woman who had been experiencing acute renal and hepatic injury and myalgia over two years of concomitant treatment with diclofenac, atorvastatin, simvastatin/fenofibrate, and several other drugs, including pantoprazole and furosemide. Our pharmacogenomic findings supported the suspicion that ADRs, most notably the multi-organ toxicity experienced by our patient, may be owed to drug-drug-gene interactions and increased bioavailability of the prescribed drugs due to slower detoxification capacity and decreased hepatic and renal elimination. We also discuss the importance of CYP polymorphisms in the biotransformation of endogenous substrates such as arachidonic acid and their modulating role in pathophysiological processes. Yet even though the risks of ADRs related to the above mentioned drugs are substantially evidenced in literature, pre-emptive pharmacogenetic analysis has not yet found its way into common clinical practice.

SUBMITTER: Bozina N

PROVIDER: S-EPMC8265195 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Drug-drug-gene interactions as mediators of adverse drug reactions to diclofenac and statins: a case report and literature review.

Božina Nada N Ganoci Lana L Simičević Livija L Gvozdanović Katarina K Domjanović Iva Klarica IK Fistrek Prlić Margareta M Križ Tena T Borić Bilušić Ana A Laganović Mario M Božina Tamara T

Arhiv za higijenu rada i toksikologiju 20210628 3

Concomitant treatment with drugs that inhibit drug metabolising enzymes and/or transporters, such as commonly prescribed statins and nonsteroidal anti-inflammatory drugs (NSAIDs), has been associated with prolonged drug exposure and increased risk of adverse drug reactions (ADRs) due to drug-drug interactions. The risk is further increased in patients with chronic diseases/comorbidities who are more susceptible because of their genetic setup or external factors. In that light, we present a case ...[more]

PMID: 34187111

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Project description:While drug-drug interactions (DDIs) and their pharmacokinetic (PK) mechanisms are well-studied prior to drug approval, severe adverse drug reactions (SADRs) caused by DDIs often remain underrecognized due to limitations in pre-marketing clinical trials. To address this gap, our study utilized a literature database, applied natural language processing (NLP) techniques, and conducted multi-source electronic health record (EHR) validation to uncover underrecognized DDI-SADR signals that warrant further investigation. PubMed abstracts related to DDIs from January 1962 to December 2023 were retrieved. We utilized PubTator Central for Named Entity Recognition (NER) to identify drugs and SADRs and employed SciFive for Relation Extraction (RE) to extract DDI-SADR signals. The extracted signals were cross-referenced with the DrugBank database and validated using logistic regression, considering risk factors including patient demographics, drug usage, and comorbidities, based on EHRs from Vanderbilt University Medical Center (VUMC) and the All of Us research program. From 160,321 abstracts, we identified 111 DDI-SADR signals. Seventeen were statistically significant (13 by one EHR and 4 by both EHR databases), with 9 being previously not recorded in the DrugBank. These included methadone-ciprofloxacin-respiratory depression, oxycodone-fluvoxamine-clonus, tramadol-fluconazole-hallucination, simvastatin-fluconazole-rhabdomyolysis, ibrutinib-amiodarone-atrial fibrillation, fentanyl-diltiazem-delirium, clarithromycin-voriconazole-acute kidney injury, colchicine-cyclosporine-rhabdomyolysis, and methadone-voriconazole-arrhythmia (odds ratios (ORs) ranged from 1.9 to 35.83, with P-values ranging from < 0.001 to 0.017). Utilizing NLP to extract DDI-SADRs from Biomedical Literature and validating these findings through multiple-source EHRs represents a pioneering approach in pharmacovigilance. This method uncovers clinically relevant SADRs resulting from DDIs that were not evident in pre-marketing trials or the existing DDI knowledge base.

Dataset Information

Drug-drug-gene interactions as mediators of adverse drug reactions to diclofenac and statins: a case report and literature review.

Publications

Drug-drug-gene interactions as mediators of adverse drug reactions to diclofenac and statins: a case report and literature review.

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