title: A Physiologically Based Pharmacokinetic Model of Amiodarone and its Metabolite Desethylamiodarone in Rats: Pooled Analysis of Published Data.
abstract: OBJECTIVE
  Amiodarone (AMD) is one of the most effective drugs for rhythm control of atrial fibrillation. The use of AMD is also associated with adverse effects in multiple tissues. Both the parent compound and its major metabolite desethylamiodarone (DEA) contribute to the drug's therapeutic and toxic action. The present study aimed to build a whole-body physiologically based pharmacokinetic (PBPK) model for AMD and DEA in rats.
  
  
  METHODS
  Pharmacokinetic data from multiple studies were collected. Some of the data were pooled together to develop the PBPK model; others were used to evaluate the model. Development of the model also involved in vitro to in vivo extrapolation based on in vitro metabolism data.
  
  
  RESULTS
  The final model consisted of 11 tissue compartments, including therapeutic target organs and those to which AMD and DEA may be harmful. Model simulations were in good agreement with the observed time courses of the drug-metabolite pair in tissues, under various dosing scenarios. The key pharmacokinetic properties of AMD, such as extensive tissue distribution, substantial storage in the fat tissue, and long half-lives in many tissues, were closely reflected.
  
  
  CONCLUSIONS
  The developed PBPK model can be regarded as the first step towards a PBPK-pharmacodynamic model that can used to mechanistically evaluate and explain the high adverse event rate and potentially to determine which factors are the primary drives for experiencing an adverse event.
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA.
authors.forename: Jing-Tao
authors.initials: JT
authors.lastname: Lu
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cai
authors.affiliation: School of Pharmacy, Hainan Medical University, Haikou, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.affiliation: Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Jia
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Ave., Memphis, TN, 38163, USA. zhu13@uthsc.edu.
authors.forename: Zhe-Yi
authors.initials: ZY
authors.lastname: Hu
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, 1428 Madison Ave, New York, NY, 10029, USA. yuansheng.zhao@gmail.com.
authors.forename: Yuan-Sheng
authors.initials: YS
authors.lastname: Zhao
mesh_terms: D000465:Algorithms; D000638:Amiodarone / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation; D001812:Blood-Brain Barrier / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006207:Half-Life; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008954:Models, Biological; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D014018:Tissue Distribution
chemical_list: D000889:Anti-Arrhythmia Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; C036116:desethylamiodarone; D000638:Amiodarone