CYCLOSPORINE-A IN FAT EMULSION CARRIERS - STUDIES ON THE IMMUNOSUPPRESSIVE POTENTIAL, USING THE HETEROTOPIC HEART-TRANSPLANT MODEL IN RATS

Cyclosporin A (CyA) is an extremely lipophilic drug that needs a solub ilizing agent to become soluble in water. In the commercially availabl e intravenous formulation - Sandimmum - Cremophor EL is used for this purpose. It is likely that Cremophor EL contributes to some of the sid e effects produced by i.v. Sandimmum. We have recently shown that if C remophor EL is replaced by a soybean oil (SBO)-based fat emulsion carr ier, the acute renal side effects following i.v. administration of CyA are avoided in a rat model. It is then important to ascertain whether the use of a fat emulsion carrier alters the immunosuppressive effect of CyA. Moreover, fatty acids can themselves influence the immune sys tem, and both omega-3 and omega-6 fatty acids have been reported to po ssess immunosuppressive properties. In the present study, the effect o n graft survival of i.v. CyA administered in five different formulatio ns, using fat emulsions or liposomes as carriers, was compared to that of conventional Sandimmum infusion substance in the heterotopic heart transplant model in rats. The new formulations tested did not reduce the immunosuppressive effect of CyA. On the contrary, a small but sign ificant increase in graft survival was noted in the groups given CyA i n the SBO-based fat emulsion carrier (17.0 +/- 0.82 days) and CyA in l iposomes (16.0 +/- 0.63 days) as compared to the results in the Sandim mun-treated group (15.0 +/- 0.58 days: P < 0.01 and P < 0.05, respecti vely).