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

Abstract

Aims: 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.

Figure 1

Amiodarone concentrations in plasma and adipose tissue. Conc., concentrations. (a) Concentrations of amiodarone in adipose tissue and in plasma, in logarithmic scale, with observations ordered by plasma concentrations. (b) Linear regression of concentrations obtained in fat tissue with regard to concentrations in plasma. (c) Linear regression of concentrations obtained in the two simultaneous samples of adipose tissue performed. (d) Bland–Altman plot displaying the difference between measures at the two different sampling points of adipose tissue against its average, in mg kg⁻¹. The limits of agreement are defined by the mean difference (medium line) +/− twice the standard deviation of the differences (top and bottom lines)

Figure 2

Relationships of amiodarone concentrations with cumulated and daily doses. Conc., concentrations. Correlations between amiodarone concentrations, in plasma and fat tissue, and maintenance and cumulated doses, adjusted by patient body weight, in Kg. Linear regression is displayed for all four analyses; nonlinear models were also explored but did not fit better