Pharmacocinétique et optimisation galénique de dithiarsolanes à visée antileucémique : exemple des nanosuspensions d'arsthinol

Abstract : The organoarsenical arsthinol (Balarsen®) was used in the 1950s in the treatment of amoebiasis and in dermatology and was considered as ?highly tolerated'. Recent investigations have shown a very good efficiency of arsthinol on leukemic cells (U937 and K562) as compared with arsenic trioxide and melarsoprol. In the present work, we have assessed the anti-leukemic activity of arsthinol on acute promyelocytic leukemia NB4 cells as compared with As2O3. Our results have shown that arsthinol and As2O3 induced growth inhibition and apoptosis at low concentrations = 5µM. Arsthinol is a promising drug for leukemia. However, this dithiarsolane is very poorly soluble in water. An alternative approach to overcoming problems such as solubility, local intolerability and risks of neurotoxicity is to develop nanosuspensions of the drug. The use of nanosuspensions of arsthinol after I.V. injection in mice has allowed us to reduce the cerebral concentration of the arsenical. In contrast, bone-marrow concentrations remained very high. Moreover, arsthinol nanosuspensions remained cytotoxic on NB4 cells. Finally, we have determined the metabolites of arsthinol in urine of mice. This study allowed us to complete the understanding on the mechanism of biotransformation and the elimination pathways of the drug.
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Imane Ajana. Pharmacocinétique et optimisation galénique de dithiarsolanes à visée antileucémique : exemple des nanosuspensions d'arsthinol. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2010. Français. ⟨NNT : 2010NAN10018⟩. ⟨tel-01775835⟩

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