Amiodarone concentrations in plasma and fat tissue during chronic treatment and related toxicity.
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.
Lafuente-Lafuente
Carmelo
C
AP-HP, Hôpital Lariboisière, Department of Internal Medicine A, Paris, France. lafuente@nodo3.net
Alvarez
Jean-Claude
JC
Leenhardt
Antoine
A
Mouly
Stéphane
S
Extramiana
Fabrice
F
Caulin
Charles
C
Funck-Brentano
Christian
C
Bergmann
Jean-François
JF
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
D000889:Anti-Arrhythmia Agents; D000638:Amiodarone