title: Metabolite identification studies on amiodarone in in vitro (rat liver microsomes, rat and human liver S9 fractions) and in vivo (rat feces, urine, plasma) matrices by using liquid chromatography with high-resolution mass spectrometry and multiple-stage mass spectrometry: characterization of the diquinone metabolite supposedly responsible for the drug's hepatotoxicity.
abstract: BACKGROUND
  Several mechanisms have been anticipated for the toxicity of amiodarone, such as oxidative stress, lipid peroxidation, phospholipidosis, free radical generation, etc. Amiodarone is structurally similar to benzbromarone, an uricosuric agent, which was withdrawn from European markets due to its idiosyncratic hepatotoxicity. A proposed reason behind the toxicity of benzbromarone was the production of a reactive ortho-diquinone metabolite, which was found to form adducts with glutathione. Therefore, taking a clue that a similar diquinone metabolite of amiodarone may be the reason for its hepatotoxicity, metabolite identification studies were carried out on the drug using liquid chromatography/mass spectrometry (LC/MS) tools.
  
  
  METHODS
  The studies involved in vitro (rat liver microsomes, rat liver S9 fraction, human liver S9 fraction) and in vivo (rat feces, urine, plasma) models, wherein the samples were analyzed by employing LC/HRMS, LC/MS(n) and HDE-MS.
  
  
  CONCLUSIONS
  A total of 26 metabolites of amiodarone were detected in the investigated in vitro and in vivo matrices. The suspected ortho-diquinone metabolite was one of them. The formation of the same might be an added reason for the hepatotoxicity shown by the drug.
authors.affiliation: Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, 160 062, Punjab, India.
authors.forename: Ninad
authors.initials: N
authors.lastname: Ramesh Varkhede
authors.forename: Shalu
authors.initials: S
authors.lastname: Jhajra
authors.forename: Deepak
authors.initials: D
authors.lastname: Suresh Ahire
authors.forename: Saranjit
authors.initials: S
authors.lastname: Singh
mesh_terms: D000638:Amiodarone / Q000031:analogs & derivatives* / Q000032:analysis* / Q000097:blood / Q000378:metabolism* / Q000633:toxicity / Q000652:urine; D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods*; D003198:Computer Simulation; D005243:Feces; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D008862:Microsomes, Liver / Q000378:metabolism*; D011809:Quinones / Q000032:analysis / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D018675:Toxicity Tests
chemical_list: D011809:Quinones; D000638:Amiodarone