Structure-effect relationships of amiodarone analogues on the inhibition of thyroxine deiodination.
OBJECTIVE
Amiodarone (AMI) has proven to be a potent anti-arrhythmic compound. Due to the structural similarity between AMI and thyroid hormone, it is possible that the drug could inhibit the activity of the 5'-thyroxine-deiodinase.


METHODS
AMI analogues resulting from (1) dealkylation, (2) deiodination and (3) deamination were synthesised and used as inhibitors in an in vitro biotransformation reaction of thyroxine (T4) to 3,3',5'-triiodothyronine (T3). Using high-performance liquid chromatography and ultraviolet detection for quantifying T3, it was found that the 5'-T4 deiodinase type I was involved in the reaction. On separate occasions, AMI or an AMI analogue was added to the reaction as an inhibitor.


RESULTS
All studied AMI analogues inhibited 5'-T4 deiodination competitively (Ki value range 25-360 microM). In the concentration range of 1-1000 microM, AMI and its N-desethylated, deiodinated analogues inhibited 5'-T4 deiodination very weakly. AMI analogues with a hydroxyl group at the 4-position were strong inhibitors. Moreover, diiodo-AMI analogues inhibited 5'-T4 deiodination more strongly than their corresponding monoiodo- or deiodinated derivatives.


CONCLUSIONS
It is likely that the degraded products of AMI could be responsible for thyroid dysfunction toxicosis in AMI therapy.
Ha
H R
HR
Department of Internal Medicine, University Hospital Zurich, Switzerland. huyriem.ha@dim.usz.ch
Stieger
B
B
Grassi
G
G
Altorfer
H R
HR
Follath
F
F
D000638:Amiodarone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D007453:Iodide Peroxidase / Q000037:antagonists & inhibitors; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013974:Thyroxine / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism*
D014284:Triiodothyronine; C109812:iodothyronine deiodinase type I; D007453:Iodide Peroxidase; D000638:Amiodarone; D013974:Thyroxine