Phospholipids as multidrug resistance modulators of the transport of epirubicin in human intestinal epithelial Caco-2 cell layers and everted gut sacs of rats

Phospholipids have been increasingly used as carriers for the delivery of a variety of drugs. Studies using cancer chemotherapeutic agents such as epirubicin encapsulated in liposomes, which are made of phospholipids and other ingredients, have generally shown reduced toxicity and enhanced therapeutic efficacy. The recent investigation of the role of P-glycoprotein (P-gp) in phospholipid translocation has opened a new area of research on the possible use of phospholipids as multidrug resistance (MDR) modulators. This study investigated the effects of liposomal encapsulation, empty liposome pretreatment, or free lipid pretreatment on the uptake and transport of epirubicin in the human colon adenocarcinoma cell line Caco-2 and in everted gut sacs of rat jejunum and ileum. Epirubicin uptake experiments, using a flow cytometer, showed that both liposomal encapsulation and empty liposome pretreatment increased the intracellular accumulation of epirubicin in Caco-2 cells significantly. These two treatments substantially increased apical-to-basolateral absorption of epirubicin across Caco-2 monolayers and markedly improved mucosal-to-serosal absorption of epirubicin in rat jejunum and ileum. Enhancement also was observed with both liposome encapsulation and empty liposome pretreatment in the reduction of basolateral-to-apical efflux of epirubicin across Caco-2 monolayers. However, because diffusion of free dipalmitoyl phosphatidylcholine (DPPC) or dipalmitoyl phosphatidylethanolamine (DPPE) lipids across the cell membrane is very slow, these free lipids showed marginal effects on absorption and/or secretion of epirubicin in both Caco-2 cells and rat gut sacs. The study suggests that inhibition of P-gp or other transporter proteins located in the intestines may be partially involved in the reduction of epirubicin efflux. In conclusion, the therapeutic efficacy of epirubicin may be improved by using phospholipids as excipients and MDR modulators in the formulations. Liposomal formulations may have important applications to circumvent drug resistance in cancer chemotherapy. (C) 2000 Elsevier Science Inc.