EFFECT OF AMIODARONE ON NON-DEIODINATIVE PATHWAY OF THYROID-HORMONE METABOLISM

Amiodarone, an iodine containing anti-arrhythmic drug, causes a significant decrease in molar ratio of daily production rates of T3 and T4 from 0.75 in controls to 0.36 in amiodarone-treated rabbits. A model was constructed from the above data which showed that metabolism of T4 via non-deiodinative pathways (e.g. tetraiodothyroacetic acid and/or conjugates) increased from 29% in untreated controls to 66% in amiodarone-treated rabbits. In this study, we have examined the metabolic clearance rate of tetraiodothyroacetic acid in rabbits given amiodarone (20 mg · kg-1 · day-1 ip for 3 weeks) or saline (controls). Serum amiodarone and desethylaminodarone levels under the above experimental conditions were 0.20 ± 0.067 and 0.17 ± 0.058 mg/l, respectively which were in the near-therapeutic range observed in humans. Control and amiodarone-treated rabbits were administered [125I]tetraiodothyroacetic acid (10 μCi/rabbit) iv and blood was collected at 0.5, 1, 2, 4, 6, 10, 32 and 48 h. Serum tetraiodothyroacetic acid radioactivity was determined by trichloroacetic acid precipitation and ethanol extraction and metabolic clearance rates were calculated from the area under the curve of computer fits to tetraiodothyroacetic acid radioactivity data. Amiodarone treatment decreased metabolic clearance rates significantly from 0.107 ± 0.008 in controls to 0.074 ± 0.009 l/day in amiodarone-treated rabbits (p < 0.05). However, when expressed per unit body weight (1 · day-1 · kg-1), the metabolic clearance rates were not significantly different between the controls and amiodarone-treated rabbits. The terminal serum elimination half-life in the two groups were similar (32.0 ± 6.7 h in controls vs 49.2 ± 12.4 h in amiodarone-treated). Our data suggest that a modest decrease in clearance rate and an increased production rate could result in an increase in serum tetraiodothyroacetic acid levels which may contribute to the reduction in 5'-monodeiodination of iodothyronines documented previously in amiodarone-treated animals. The marginal decrease in metabolic clearance rate of tetraiodothyroacetic acid found in this study suggests that the two-fold increase in the conversion of T4 metabolism to non-deiodinated metabolites/conjugates in amiodarone-treated rabbits results predominantly from an increase in production rate of tetraiodothyroacetic acid.