TIME-COURSE OF CYCLOSPORINE AND ITS METABOLITES IN BLOOD, LIVER AND SPLEEN OF NAIVE LEWIS RATS - COMPARISON WITH PRELIMINARY DATA OBTAINED IN TRANSPLANTED ANIMALS

The time course of intravenously administered cyclosporine (1 mg kg(-1 )) and its metabolites AMI, AM9, and AM1c were examined in the blood, liver, and spleen of naive Lewis rats. Cyclosporine concentration vers us time data for all three tissues were qualitatively similar, followi ng a biexponential model C=Ae(-lambda 1t)+Be-(lambda 2t) with maximum cylosporine concentrations reached at Ih. Whole-blood cyclosporine cle arance, terminal half-life, mean residence time, steady state volume o f distribution, and hepatic extraction ratio (calculated from blood da ta) were similar to previously reported results. Cyclosporine in the l iver showed the largest area under the concentration-time curve, mean residence time, and disposition and terminal half-lives. Spleen cyclos porine mean residence time and terminal half-life were not significant ly different from blood parameters. Metabolites AM1, AM9, and AM1c sho wed almost parallel time courses in all three tissues. The hydroxylate d derivative AM9 was the major metabolite found in all tissues, with t wofold greater levels in the liver compared to the blood and the splee n. Slightly less AM1 was found in the liver relative to blood and sple en, where it was present in equal amounts. AM1c levels in the liver we re not different from those in the spleen and were greater than observ ed for blood. The results obtained above were reflected in preliminary studies using liver transplanted rats treated with multiple doses of cyclosporine. Both blood and liver biopsy levels of CyA, AMI, and AM9 post-transplant showed twofold to fourfold decreases from day 3 (sampl es taken 4h post-Cyt-dose) to day 7 (samples taken 24h post-CyA-dose) and concentrations were not significantly different from similarly sam pled naive controls. More importantly, the metabolite/CyA ratios did n ot vary significantly between liver and blood in the two groups. For n aive rats, and liver transplanted animals not undergoing rejection, ch anges in blood cyclosporine levels seem to predict variations in tissu e concentrations.