Pulmonary sequestration of amiodarone and desethylamiodarone
Camus, P.; Mehendale, H.M.
Journal of Pharmacology and Experimental Therapeutics 237(3): 867-873
1986
ISSN/ISBN: 0022-3565 PMID: 3712283 Document Number: 286031
We hypothesized that one of the reasons for the particular susceptibility of the lung toward the adverse effects from the antiarrhythmic agent amiodarone (A) could be a high pulmonary accumulation of this drug. This hypothesis was tested using the isolated perfused lungs of Fischer 344 and Sprague-Dawley rats and New Zealand White rabbits. Uptake of 3 .mu.M starting concentration of a mixture of A and [14C]A by the lung occurred rapidly in each species, and only 25.6, 19 and 16.4% of the initial concentration remained in the perfusate at the end (60 min) of the experiment in Fischer 344, Sprague-Dawley rats and rabbits, respectively. No metabolism of A was detected by the high-performance liquid chromatography technique. Raising the initial concentration of A from 0.3 to 120 .mu.M (n = 26) in the Fischer 344 rats apparently did not saturate the uptake process, and the tissue/medium ratio averaged 122.5. The uptake of desethylamiodarone (DEA), the main metabolite of A in vivo, was more extensive (tissue/medium ratio = 506) than that of the parent compound. DEA also was not metabolized by the isolated perfused lungs. Lung homogenate incubations fortified with cofactors did not metabolize A or DEA. We conclude that in the isolated perfused lungs: 1) A is extensively taken up by the lungs of rats and rabbits; 2) the uptake is not saturated by raising the concentrations over a 400-fold range; 3) DEA is taken up more readily than A; and 4) metabolism of neither compound is observed.