THE INCREASED EFFICACY AND DECREASED NEPHROTOXICITY OF A CYCLOSPORINELIPOSOME

A potential approach to avoid the complications of systemic immunosupp ression is to deliver immunosuppressive agents locally to the site of the allograft. Liposomes are phospholipid particles that allow deliver y of drugs preferentially to the reticuloendothelial system. Since the liver is a primary component of the RES, we hypothesized that liposom e technology could be utilized to deliver immunosuppressive agents loc ally to a transplanted liver, thereby avoiding the complications of sy stemically delivered immunosuppression. We evaluated this hypothesis w ith a prototypic cyclosporine liposome in a rat model. Pharmacokinetic studies of this liposome indicated earlier clearance from the systemi c circulation and increased hepatic uptake relative to the standard in travenous form of CsA. Decreased nephrotoxicity was also shown in an i schemic kidney model in the rat. The immunosuppressive efficacy of thi s liposome was also tested in a rat liver transplant model. There was a significant increase in survival compared with standard intravenous CsA when both drugs were administered at a dose of 1.75 mg/kg/day for seven days posttransplant (P<.05, CsA liposome-treated versus CsA/sali ne-treated). There were no demonstrable early toxic effects or late to xic effects observed with follow-up to 100 days. These data indicate t hat CsA liposomes have potential for use as an immunosuppressive agent with increased efficacy and decreased nephrotoxicity relative to the commercially available form of intravenous CsA. This improved therapeu tic index of a locally targeted drug may lead to fewer complications a ttributed to systemic immunosuppression.