Amiodarone concentrations in plasma and fat tissue during chronic treatment and related toxicity

WHAT IT IS ALREADY KNOW ABOUT THIS SUBJECT center dot Amiodarone is a highly effective antiarrhythmic drug, but is limited in practice by its adverse effects, which are frequent on long-term administration and can be severe. center dot Amiodarone is very lipophilic and attains high concentrations in many tissues. center dot Excessive accumulation in tissues is suspected as a possible cause of some of its adverse events, but sampling affected tissues (e.g. lung, thyroid, heart) in vivo is difficult. center dot Subcutaneous adipose tissue is more easily obtained, and studying concentrations of amiodarone and N-desethyl-amiodarone there could help to understand how amiodarone distributes and accumulates in tissues in general. WHAT THIS STUDY ADDS center dot No evidence of excessive or unexpected accumulation of amiodarone in fat tissue, with respect to dose, was found in patients treated for > 3 months. center dot Concentrations in plasma and subcutaneous fat tissue were better related to maintenance daily dose than to cumulated dose or treatment duration. center dot Clinically relevant adverse effects of amiodarone, for the most part hypothyroidism, were significantly associated with longer duration of treatment and larger cumulated doses. center dot In contrast, adverse events were not correlated with higher amiodarone or N-desethyl-amiodarone concentrations, whether in plasma or in adipose subcutaneous tissue. center dot The measurement of these concentrations does not seem useful in predicting the risk of adverse effects. 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. 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. 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 >= 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. 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.