Investigation of amodiaquine localization in liver lobules using matrix-assisted laser desorption/ionization imaging mass spectrometry.

RATIONALE: High mass and high spatial resolution matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) opens new possibilities for the detailed study of the hepatic metabolism of drugs. The spatial and temporal distribution of drug metabolites within liver lobules, anatomical subunits of the liver, may aid in the understanding of the formation of reactive metabolites that bind to liver proteins and cause drug-induced liver injury.

METHODS

Frozen livers obtained from rats dosed orally with amodiaquine (100 mg/kg) were sectioned at 10 μm and coated with a MALDI matrix. The liver sections were then analyzed using a Fourier transform ion cyclotron resonance mass spectrometer. Images corresponding to amodiaquine and its metabolites were obtained at a spatial resolution of 25 μm.

RESULTS

Molecular images of amodiaquine within liver lobules have higher intensities near the portal triad and lower intensities near the central vein.

CONCLUSIONS

This study demonstrates that MALDI IMS can be used to investigate the metabolism of drugs within liver lobules. The results are consistent with existing knowledge of amodiaquine metabolism and reactive metabolite formation.