Comparison of nanosuspensions and hydroxypropyl-β-cyclodextrin complex of melarsoprol: Pharmacokinetics and tissue distribution in mice

The aim of this work was to develop and compare two formulations of melarsoprol (nanosuspension and hydroxypropyl-beta-cyclodextrin inclusion complex). The arsenic concentrations in the organs have been assessed on a mouse model. Since this organoarsenical drug has been proposed for the treatment of cerebral trypanosomiasis and refractory leukaemias, special emphasis has been put on the bone marrow and on the brain. The organic solution of melarsoprol (Mel B, 0.039 mmol/kg), injected intravenously as control formulation, was found to concentrate significantly in the bone marrow (C-max = 1.64 mmol/g), though, not surprisingly, the brain concentration was quite high (C-max = 0.093 mmol/g) and the LD50 was 0.12 mmol/kg. The hydroxypropyl-beta-cyclodextrin inclusion complex was found to concentrate much more in the brain (C-max = 0.25 mmol/g) leading to a higher acute toxicity (i.e., lower LD50; 0.056 mmol/kg). Nevertheless, even if the encephalopathy risk has to be taken in to account, this could be considered as a positive point for the treatment of the cerebral trypanosomiasis, which is the main indication for this drug. On the contrary, the use of nanosuspensions allowed us to reduce the cerebral concentration (C-max = 0.02 mu mol/g) and the acute toxicity (LD50 = 0.25 mmol/kg). Moreover, nanosuspensions, especially those prepared with polxamer 407, preserved a good in vitro antileukemic activity (IC50 = 3.34 +/- 0.33 after 48 h on K562) with high bone marrow concentrations (C-max = 1.85 mu mol/g). As a consequence this formulation could be proposed for the treatment of refractory leukaemias. (C) 2008 Elsevier B.V. All rights reserved.