Effect of PSC 833 liposomes and Intralipid on the transport of epirubicin in Caco-2 cells and rat intestines

Clinical applications of first-generation multidrug resistance (MDR) modula tors, such as cyclosporin A (CsA) have been hampered because of their sever e side effects in vivo. Recent investigations have led to the development o f a more potent and less toxic modulator, PSC 833, which is a nonimmunosupp ressive analogue of CsA. However, adverse pharmacokinetic interactions betw een anticancer drugs and PSC 833 have resulted in increased toxicity as com pared to the individual toxicity. Our study evaluated the MDR reversing eff ect of PSC 833 in free, liposomal or Intralipid formulations on the uptake and transport of epirubicin in Caco-2 cells and everted gut sacs of rats. T he results showed that PSC 833 in free or liposomal formulations significan tly enhanced the intracellular accumulation of epirubicin in a dose-related manner in Caco-2 cells. The optimum in enhancement was observed at the con centration of 2 muM PSC 833. These formulations markedly increased the apic al to basolateral absorption of epirubicin in Caco-2 cells and substantiall y improved the mucosal to serosal absorption of epirubicin in rat jejunum a nd ileum. PSC 833 in free, liposomal or Intralipid formulations all signifi cantly reduced basolateral to apical efflux of epirubicin across Caco-2 mon olayers. However, PSC 833 in liposomes showed greater enhancement than othe r formulations. In conclusion, PSC 833 and PSC 833 liposomes have the funct ion as MDR reversing agents for the inhibition of intestinal P-glycoprotein . Liposomal preparations of PSC833 may provide a useful alternative dosage form for intravenous administration of PSC 833 to be combined with anticanc er drugs to circumvent drug resistance in cancer chemotherapy. (C) 2001 Els evier Science B.V. All rights reserved.