Identification and Mechanistic Investigation of Drug–Drug Interactions Associated With Myopathy: A Translational Approach. Issue 3 (September 2015)

• Record Type: Journal Article
• Authors: Han, X; Quinney, SK; Wang, Z; Zhang, P; Duke, J; Desta, Z; Elmendorf, JS; Flockhart, DA; Li, L
• Is Part Of: Clinical pharmacology & therapeutics. Volume 98:Issue 3(2015:Sep.)
• Page Start: 321
• Page End: 327
• Publication Date: 2015-09
• Subjects: Pharmacology -- Periodicals; Therapeutics -- Periodicals; 615.5
• DOI: 10.1002/cpt.150
• Languages: English
• ISSNs: 0009-9236

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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). <italic>In vitro</italic> 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 <italic>in vitro</italic> 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.</p> </abstract>