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Amiodarone: A Phospholipidosis inducing Drug

Amiodarone is a drug to treat life-threatening tachycardia. Due to toxic side effects it is used only as a last resort. Amiodarone is a potent inhibitor of the lysosomal phospholipase A1 resulting in phospholipid accumulations mainly in the lung but also in the liver. The major toxic effects can be seen in the liver (mild to severe) but also in the lung.

Structure of amiodarone

As amiodarone is known to have an extremly high potential of inducing phospholipidosis, a single-dose animal study was performed to validate the increase of PAG levels in urine. The study was performed with 5 control animals an 5 animals dosed with 1000mg/kg amiodarone. The relative concentration levels of the two groups are shown in the figure below. It is obvious that after dosing (time point 0h) the PAG levels of the dosed animals increase. Interestingly, even after 120h no recovery is visible, and the mean concentration levels of the dosed animals are 10-fold increased. The rather high standared deviatons for the concentration levels of the dosed animals can be traced back to different response kinetics of the various animals (fast and slow responders).

Mean PAG levels and standard deviations for the amiodarone study. PAG levels of dosed animals are colored in black, PAG levels of control animals are colored in green.

Besides of the up-regulation of PAG in urine, a number of metabolites down-regulated in the urine of dosed animals were identified. These metabolites are all inter-mediates of the Krebs cycle. Thereby the complete Krebs cycle is down-regulated (all metabolites of the Krebs cycle are down-regulated, which are visible in urine by Metabonomics). Although the down-regulation of citrate cycle intermediates can be often seen for adverse drug effects, it is proposed in literature that for phospholipidosis a down-regulation only occurs in the case of associated organ toxicity. Histopathology confirmed phospholipidosis depositon and organ toxicity for this study.

Down-regulated metabolites in urine, which are all intermediated of the citrate cycle (Krebs cycle).


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