title: Amiodarone concentrations in plasma and fat tissue during chronic treatment and related toxicity.
abstract: OBJECTIVE
  To determine if amiodarone, highly lipophilic, accumulates in excess with respect to dose in fat tissue during long-term administration, and study if plasma and fat tissue concentrations are correlated with adverse effects.
  
  
  METHODS
  Trough concentrations of amiodarone and N-desethyl-amiodarone were measured simultaneously in plasma and fat tissue, in 30 consecutive patients treated with amiodarone for 3 months to 12 years. Subcutaneous adipose tissue was obtained by needle aspiration from lumbar and abdominal areas. Concentrations were measured by liquid chromatography-tandem mass spectrometry.
  
  
  RESULTS
  Plasma levels of amiodarone and N-desethyl-amiodarone were significantly correlated with daily maintenance doses (R= 0.52, P= 0.003). Amiodarone concentrations in fat tissue were four to 226 times (mean 55) higher than in plasma, and well correlated with plasma levels (R= 0.68, P < 0.001). Concentrations of amiodarone and N-desethyl-amiodarone in adipose tissue did not significantly increase with higher total cumulated doses or longer treatment duration. Nine of 12 patients who had received amiodarone for > or =2 years developed clinically important adverse effects, predominantly hypothyroidism (n= 6), compared with two of 18 patients treated for less time (relative risk 6.75; 95% confidence interval 1.8, 26). The incidence of those adverse effects was not significantly associated with amiodarone concentrations, whether in plasma or in adipose tissue.
  
  
  CONCLUSIONS
  We found no evidence of excessive or unexpected accumulation of amiodarone in fat tissue on long-term administration. Late amiodarone adverse effects, particularly hypothyroidism, are associated with longer exposure times, but do not seem to be explained by higher concentrations in plasma or in fat tissue.
authors: AP-HP, Hôpital Lariboisière, Department of Internal Medicine A, Paris, France. lafuente@nodo3.net
authors: Carmelo
authors: C
authors: Lafuente-Lafuente
authors: Jean-Claude
authors: JC
authors: Alvarez
authors: Antoine
authors: A
authors: Leenhardt
authors: Stéphane
authors: S
authors: Mouly
authors: Fabrice
authors: F
authors: Extramiana
authors: Charles
authors: C
authors: Caulin
authors: Christian
authors: C
authors: Funck-Brentano
authors: Jean-François
authors: JF
authors: Bergmann
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000638:Amiodarone / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics; D005260:Female; D006331:Heart Diseases / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010949:Plasma; D012307:Risk Factors
chemical_list: D000889:Anti-Arrhythmia Agents; D000638:Amiodarone