Abstract:
Asulacrine (ASL) is an inhibitor of topoisomerase II, which has shown potential against breast and lung cancer. It is a poorly water soluble drug. To allow intravenous (i.v.) administration, ASL was formulated as a nanocrystalline suspension by high pressure homogenization. The nanosuspension was lyophilized to obtain the dry ASL nanoparticles (average size, 133+/-20nm), which enhanced both the physical and chemical stability of the ASL nanoparticles. ASL dissolution and saturation solubility were enhanced by the nanosuspension. Differential scanning calorimetry and X-ray diffraction analysis showed that the crystallinity of the ASL was preserved during the high pressure homogenization process. The pharmacokinetics and tissue distribution of ASL administered either as a nanosuspension or as a solution were compared after i.v. administration to mice. In plasma, ASL nanosuspension exhibited a significantly (P<0.01) reduced C(max) (12.2+/-1.3microg ml(-1)vs 18.3+/-1.0microg ml(-1)) and AUC(0-infinity) (18.7+/-0.5microg ml(-1)h vs 46.4+/-2.6microg ml(-1)h), and a significantly (P<0.01) greater volume of distribution (15.5+/-0.6lkg(-1)vs 2.5+/-0.1lkg(-1)), clearance (1.6+/-0.04lh(-1)kg(-1)vs 0.6+/-0.04lh(-1)kg(-1)) and elimination half-life (6.1+/-0.1h vs 2.7+/-0.2h) compared to the ASL solution. In contrast, the ASL nanosuspension resulted in a significantly greater AUC(0-infinity) in liver, lung and kidney (all P<0.01), but not in heart.
