PubMed · 9509054
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H Swanton. Amiodarone.. https://pubmed.ncbi.nlm.nih.gov/9509054/
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Amiodarone, an antiarrhythmic drug toxic toward the lung, is metabolized through sequential modifications of the diethylaminoethoxy group to mono-N-desethylamiodarone (MDEA), di-N-desethylamiodarone (DDEA), and amiodarone-EtOH (B2-O-EtOH), whose effects on lung cells are unclear. To clarify this, we exposed rabbit alveolar macrophages to analogs with different modifications of the diethylaminoethoxy group and then searched for biochemical signs of cell damage, formation of vacuoles and inclusion bodies, and interference with the degradation of surfactant protein A, used as a tracer of the endocytic pathway. The substances studied included MDEA, DDEA, and B2-O-EtOH, analogs with different modifications of the diethylaminoethoxy group, fragments of the amiodarone molecule, and the antiarrhythmic agents dronedarone (SR-33589) and KB-130015. We found the following: 1). MDEA, DDEA, and B2-O-EtOH rank in order of decreasing toxicity toward alveolar macrophages, indicating that dealkylation and deamination of the diethylaminoethoxy group represent important mechanisms of detoxification; 2). dronedarone has greater, and KB-130015 has smaller, toxicity than amiodarone toward alveolar macrophages; and 3). the benzofuran moiety, which is toxic to liver cells, is not directly toxic toward alveolar macrophages.
OBJECTIVE: To report a case of severe myopathy associated with concomitant simvastatin and amiodarone therapy. CASE SUMMARY: A 63-year-old white man with underlying insulin-dependent diabetes, recent coronary artery bypass surgery, and postoperative hemiplegia was treated with aspirin, metoprolol, furosemide, nitroglycerin, and simvastatin. Due to recurrent atrial fibrillation, oral anticoagulation with phenprocoumon and antiarrhythmic treatment with amiodarone were initiated. Four weeks after starting simvastatin 40 mg/day and 2 weeks after initiating amiodarone 1 g/day for 10 days, then 200 mg/day, he developed diffuse muscle pain with generalized muscular weakness. Laboratory investigations revealed a significant increase of creatine kinase (CK) peaking at 40 392 U/L. Due to a suspected drug interaction of simvastatin with amiodarone, both drugs were stopped. CK normalized over the following 8 days, and the patient made an uneventful recovery. An objective causality assessment revealed that the myopathy was probably related to simvastatin. DISCUSSION: Myopathy is a rare but potentially severe adverse reaction associated with statins. Besides high statin doses, concomitant use of fibrates, defined comorbidities, and concurrent use of inhibitors of cytochrome P450 are important additional risk factors. This is especially relevant if statins predominantly metabolized by CYP3A4 are combined with inhibitors of this isoenzyme. Amiodarone is a potent inhibitor of several different CYP isoenzymes, including CYP3A4. CONCLUSIONS: Avoiding the concomitant use of drugs with the potential to inhibit CYP-dependent metabolism (eg, amiodarone) or elimination of statins may decrease the risk of statin-associated myopathy. Alternatively, if drug therapy with a potent CYP inhibitor is inevitable, choosing a statin without relevant CYP metabolism (eg, pravastatin) should be considered.
Amiodarone (AMI) is frequently used for the treatment of supraventricular arrhythmias. The parent drug is rapidly dealkylated to mono-N-desethylamiodarone (MDEA) and the plasma concentrations of AMI and MDEA are comparable. MDEA is a secondary amine and may thus undergo formation to the corresponding N-nitrosamine in combination with coadministered nitrovasodilators. Previous studies have shown that nitrovasodilators release the vasoactive NO? which may nitrosylate thiol or secondary amine groups in aqueous solutions. Therefore, the nitrosylation potential of MDEA at physiological pH was investigated. N-Nitroso-monodesethylamiodarone (NO-MDEA) was synthesized, characterized and used as a reference product for the detection of the corresponding N-nitrosamine. HPLC and NMR results have shown that the NO-MDEA product is an equilibrium of two configurational isomers (syn and anti). NO-release was generated by sodium nitroprusside (SNP) which was exposed to light. The formation to NO-MDEA was assayed by HPLC-UV. It has been found that MDEA is nitrosylated in the higher nanomolar range and that varying oxygenation of the reaction mixture did not significantly affect the reaction yields. The addition of thiols such as serum albumin (0.6mM), l-cysteine (2.5mM) or N-acetylcysteine (2.5mM) inhibited the NO-MDEA formation indicating that they may prevent N-nitrosamine formation in vivo. However, as S-nitrosothiols may also release NO?, in long term exposure to elevated levels of nitric oxide the nitrosylation of secondary amines may be taken into account.