The effect of ischemic liver damage on ciclosporin metabolism

Abstract

Ciclosporin has great immunosuppressive potency and it has become the immunosuppressive agent of first choice in most transplant centers. But its therapeutic index is very narrow, the individual therapeutic response and the bioavailability are both very variable. Therefore, regular monitoring of ciclosporin blood level is required.
Ciclosporin is chiefly metabolised by cytochrome p-450 in liver. So, in liver transplantation, ischemic damage, surgical complications and graft rejection are direct and severe to the most important organ of ciclosporin metabolism. The optimal use of ciclosporin is more difficult, and the study of ciclosporin metabolism is very important issue.
The effect of ischemic liver damage on ciclosporin metabolism in dogs was examined. Liver ischemia was made by total vascular occulusion of porta hepatica, and the ciclosporin concentration in whole blood and in bile were measured by high performance liquid chromatography (HPLC) and radioimmunoassay (RIA).
The concentration of ciclosporin in whole blood study increased only a little, also increased in bile study, but the amount of ciclosporin excretion in bile decreased with ischemic damage. RIA was not efficient method to measure ciclosporin metabolites and more specific method such as HPLC should be used.
Three peakes on the chromatograph of bile samples were successfully quantitated. These are probably ciclosporin metabolites (M1, M17 and M21). The concentration and the biliary excretion of two peaks (M17 and M1: hydroxylated) markedly increased and those of one peak (M21: N-demethylated) markedly decreased. Possibly the severerity of ischemic damage is not equal to each metabolic pathway.