title: Identification and Mechanistic Investigation of Drug-Drug Interactions Associated With Myopathy: A Translational Approach.
abstract: Myopathy is a group of muscle diseases that can be induced or exacerbated by drug-drug interactions (DDIs). We sought to identify clinically important myopathic DDIs and elucidate their underlying mechanisms. Five DDIs were found to increase the risk of myopathy based on analysis of observational data from the Indiana Network of Patient Care. Loratadine interacted with simvastatin (relative risk 95% confidence interval [CI] = [1.39, 2.06]), alprazolam (1.50, 2.31), ropinirole (2.06, 5.00), and omeprazole (1.15, 1.38). Promethazine interacted with tegaserod (1.94, 4.64). In vitro investigation showed that these DDIs were unlikely to result from inhibition of drug metabolism by CYP450 enzymes or from inhibition of hepatic uptake via the membrane transporter OATP1B1/1B3. However, we did observe in vitro synergistic myotoxicity of simvastatin and desloratadine, suggesting a role in loratadine-simvastatin interaction. This interaction was epidemiologically confirmed (odds ratio 95% CI = [2.02, 3.65]) using the data from the US Food and Drug Administration Adverse Event Reporting System.
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University at Indianapolis, Indianapolis, Indiana, USA.|Center for Computational Biology and Bioinformatics, Indiana University at Indianapolis, Indianapolis, Indiana, USA.|Division of Clinical Pharmacology in the Department of Medicine, Indiana University at Indianapolis, Indianapolis, Indiana, USA.
authors.forename: X
authors.initials: X
authors.lastname: Han
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University at Indianapolis, Indianapolis, Indiana, USA.|Department of Obstetrics and Gynecology, Indiana University at Indianapolis, Indianapolis, Indiana, USA.|Indiana Institute of Personalized Medicine, School of Medicine, Indiana University at Indianapolis, Indianapolis, Indiana, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Quinney
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University at Indianapolis, Indianapolis, Indiana, USA.|Department of Medical and Molecular Genetics, Indiana University at Indianapolis, Indianapolis, Indiana, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University at Indianapolis, Indianapolis, Indiana, USA.
authors.forename: P
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Regenstrief Institute, Indiana University at Indianapolis, Indianapolis, Indiana, USA.
authors.forename: J
authors.initials: J
authors.lastname: Duke
authors.affiliation: Division of Clinical Pharmacology in the Department of Medicine, Indiana University at Indianapolis, Indianapolis, Indiana, USA.|Indiana Institute of Personalized Medicine, School of Medicine, Indiana University at Indianapolis, Indianapolis, Indiana, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Desta
authors.affiliation: Department of Cellular & Integrative Physiology, Indiana University at Indianapolis, Indianapolis, Indiana, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Elmendorf
authors.affiliation: Division of Clinical Pharmacology in the Department of Medicine, Indiana University at Indianapolis, Indianapolis, Indiana, USA.|Indiana Institute of Personalized Medicine, School of Medicine, Indiana University at Indianapolis, Indianapolis, Indiana, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Flockhart
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University at Indianapolis, Indianapolis, Indiana, USA.|Division of Clinical Pharmacology in the Department of Medicine, Indiana University at Indianapolis, Indianapolis, Indiana, USA.|Department of Medical and Molecular Genetics, Indiana University at Indianapolis, Indianapolis, Indiana, USA.|Regenstrief Institute, Indiana University at Indianapolis, Indianapolis, Indiana, USA.
authors.forename: L
authors.initials: L
authors.lastname: Li
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems; D000818:Animals; D001692:Biological Transport; D001711:Biotransformation; D002460:Cell Line; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004357:Drug Synergism; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology / Q000378:metabolism; D016017:Odds Ratio; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D018570:Risk Assessment; D012307:Risk Factors; D057170:Translational Research, Biomedical / Q000379:methods*; D014481:United States / Q000453:epidemiology; D014486:United States Food and Drug Administration
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D027361:Organic Anion Transporters