caa a22 4500 475817966 CHVBK 20180406123814.0 cr unu---uuuuu 170329e20000301xx s 000 0 eng 10.1007/s002280050701 doi (NATIONALLICENCE)springer-10.1007/s002280050701 Structure-effect relationships of amiodarone analogues on the inhibition of thyroxine deiodination [Elektronische Daten] [H. R. Ha, B. Stieger, G. Grassi, H. R. Altorfer, F. Follath] Objectives: 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 (K i value range 25-360 μM). In the concentration range of 1-1000 μM, 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. Conclusion: It is likely that the degraded products of AMI could be responsible for thyroid dysfunction toxicosis in AMI therapy. Springer-Verlag Berlin Heidelberg, 2000 Key words Amiodarone analogues nationallicence 5′-T4 deiodinase nationallicence Deiodination nationallicence Ha H. R. Cardiovascular Therapy Research Unit, HLab 10, Department of Internal Medicine, University Hospital Zurich, Ramistrasse 100, CH-8091 Zurich, Switzerland e-mail: huyriem.ha@dim.usz.ch Tel.: +41-1-2553701; Fax: +41-1-2554445, CH aut Stieger B. Clinical Pharmacology and Toxicology Division, Department of Internal Medicine, University Hospital Zurich, Switzerland, CH aut Grassi G. Physical Chemistry Laboratory, Swiss Federal Institute of Technology (ETH), Switzerland, CH aut Altorfer H. R. School of Pharmacy, Swiss Federal Institute of Technology (ETH), Switzerland, CH aut Follath F. Cardiovascular Therapy Research Unit, HLab 10, Department of Internal Medicine, University Hospital Zurich, Ramistrasse 100, CH-8091 Zurich, Switzerland e-mail: huyriem.ha@dim.usz.ch Tel.: +41-1-2553701; Fax: +41-1-2554445, CH aut https://doi.org/10.1007/s002280050701 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s002280050701 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Ha H. R. Cardiovascular Therapy Research Unit, HLab 10, Department of Internal Medicine, University Hospital Zurich, Ramistrasse 100, CH-8091 Zurich, Switzerland e-mail: huyriem.ha@dim.usz.ch Tel.: +41-1-2553701; Fax: +41-1-2554445, CH aut NATIONALLICENCE 700 1- Stieger B. Clinical Pharmacology and Toxicology Division, Department of Internal Medicine, University Hospital Zurich, Switzerland, CH aut NATIONALLICENCE 700 1- Grassi G. Physical Chemistry Laboratory, Swiss Federal Institute of Technology (ETH), Switzerland, CH aut NATIONALLICENCE 700 1- Altorfer H. R. School of Pharmacy, Swiss Federal Institute of Technology (ETH), Switzerland, CH aut NATIONALLICENCE 700 1- Follath F. Cardiovascular Therapy Research Unit, HLab 10, Department of Internal Medicine, University Hospital Zurich, Ramistrasse 100, CH-8091 Zurich, Switzerland e-mail: huyriem.ha@dim.usz.ch Tel.: +41-1-2553701; Fax: +41-1-2554445, CH aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer