Characterization of In Vitro and In Vivo Metabolism of Antazoline Using Liquid Chromatography-Tandem Mass Spectrometry.
Joanna GiebułtowiczNatalia KorytowskaRoman PiotrowskiPiotr KułakowskiGniewomir LataczEwa SzymanskaBarbara WiśniowskaSebastian PolakPublished in: International journal of molecular sciences (2020)
Antazoline (ANT) was recently shown to be an effective and safe antiarrhythmic drug in the termination of atrial fibrillation. However, the drug is still not listed in clinical guidelines. No data on ANT metabolism in humans is available. We used liquid chromatography coupled with tandem mass spectrometry to identify and characterize metabolites of ANT. We analyzed plasma of volunteers following a single intravenous administration of 100 mg of ANT mesylate and in in vitro cultures of human hepatocytes. We revealed that ANT was transformed into at least 15 metabolites and we investigated the role of cytochrome P450 isoforms. CYP2D6 was the main one involved in the fast metabolism of ANT. The biotransformation of ANT by CYP2C19 was much slower. The main Phase I metabolite was M1 formed by the removal of phenyl and metabolite M2 with hydroxyl in the para position of phenyl. Glucuronidation was the leading Phase II metabolism. Further study on pharmacokinetics of the metabolites would allow us to better understand the activity profile of ANT and to predict its potential clinical applications. Ultimately, further investigation of the activity profile of the new hydroxylated M2 metabolite of ANT might result in an active substance with a different pharmacological profile than the parent molecule, and potentially a new drug candidate.
Keyphrases
- tandem mass spectrometry
- liquid chromatography
- liquid chromatography tandem mass spectrometry
- simultaneous determination
- ms ms
- atrial fibrillation
- phase ii
- clinical trial
- endothelial cells
- solid phase extraction
- high performance liquid chromatography
- mass spectrometry
- heart failure
- randomized controlled trial
- high resolution mass spectrometry
- open label
- gas chromatography
- high resolution
- adverse drug
- electronic health record
- machine learning
- big data
- left atrial
- liver injury
- left atrial appendage
- oral anticoagulants
- double blind
- chronic myeloid leukemia
- direct oral anticoagulants
- data analysis