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Effects of metabolites and analogs of amiodarone on alveolar macrophages: structure-activity relationship

Daniela Quaglino1, Huy Riem Ha, Elena Duner

  • 1Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena.

American Journal of Physiology. Lung Cellular and Molecular Physiology
|April 13, 2004
PubMed

Insights

Amiodarone metabolites like MDEA and DDEA show decreasing toxicity to lung cells, indicating detoxification pathways. Dronedarone is more toxic than amiodarone, while KB-130015 is less toxic.

Area of Science:

  • Pharmacology
  • Toxicology
  • Cell Biology

Background:

  • Amiodarone is an antiarrhythmic drug known for lung toxicity.
  • Its metabolites, including MDEA, DDEA, and B2-O-EtOH, have unclear effects on lung cells.
  • Understanding metabolite toxicity is crucial for assessing amiodarone's overall risk.

Purpose of the Study:

  • To investigate the toxicity of amiodarone metabolites on rabbit alveolar macrophages.
  • To compare the toxicity of amiodarone and its analogs, including dronedarone and KB-130015.
  • To elucidate the role of the diethylaminoethoxy group and benzofuran moiety in amiodarone's cellular effects.

Main Methods:

  • Exposure of rabbit alveolar macrophages to amiodarone analogs and fragments.
  • Assessment of biochemical markers for cell damage.
  • Evaluation of vacuole and inclusion body formation.
  • Measurement of surfactant protein A degradation as an indicator of endocytic pathway function.

Main Results:

  • Toxicity order of amiodarone metabolites: MDEA > DDEA > B2-O-EtOH, suggesting detoxification via dealkylation/deamination.
  • Dronedarone exhibited higher toxicity than amiodarone, while KB-130015 showed lower toxicity.
  • The benzofuran moiety, toxic to liver cells, was not directly toxic to alveolar macrophages.

Conclusions:

  • Metabolism of the diethylaminoethoxy group detoxifies amiodarone, reducing lung cell toxicity.
  • Dronedarone's increased toxicity warrants further investigation.
  • The benzofuran core is not the primary driver of amiodarone's direct alveolar macrophage toxicity.

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