Clinical applications of the first-generation multidrug resistance (MDR) modulators, such as cyclosporin A (CsA) have been hampered because of their severe side effects in vivo. In this study, we utilized liposomes and Intralipid to provide selective delivery of CsA to tumor cells as well as to circumvent toxicities associated with CsA by altering the pharmacodistribution properties of encapsulated CsA. The MDR reversing effect of CsA in free, liposomal or Intralipid formulations on the uptake and transport of epirubicin in Caco-2 cells and rat intestines was evaluated. The results showed that CsA in free or liposomal formulations significantly enhanced the intracellular accumulation of epirubicin in a dose-related fashion in Caco-2 cells, with the highest enhancement at 2 microM: These formulations substantially ameliorated the apical to basolateral absorption of epirubicin in Caco-2 cells and markedly increased mucosal to serosal absorption of epirubicin in rat jejunum and ileum. CsA in free, liposomal or Intralipid formulations all significantly reduced basolateral to apical efflux of epirubicin across Caco-2 monolayers. CsA encapsulated in liposomes showed greater enhancement than other formulations. In conclusion, liposomal preparations of CsA may circumvent MDR and have the advantage of diminishing side effects, thus providing a useful alternative dosage form for intravenous administration of CsA to be combined with cytotoxic agents for the treatment of resistant tumors.