BILE AND BLOOD RATIOS OF CYCLOSPORINE AND ITS METABOLITES IN PATIENTSON CONTINUOUS-INFUSION DURING THE FIRST 3 WEEKS AFTER LIVER-TRANSPLANTATION

Ten patients with orthotopic liver transplants were investigated durin g routine therapeutic monitoring to study the relationship between the concentrations of cyclosporin and its metabolites in blood, bile and urine, and whether this information can provide early signs of severe hepatic disorders post-transplantation. Cyclosporin (Sandimmun(R)) was administered by continuous infusion at a constant rate of 5 mg/kg/day , modified to keep the blood cyclosporin concentration within the targ et range (400 to 500 mu g/L). The concentrations of cyclosporin and co mbined cyclosporin-metabolites in blood, bile and urine were assayed d aily during the 3 post-transplantation weeks that the patients spent i n intensive care. All patients developed cholestatis and cytolysis dur ing the first week. The severity of these liver transplant disorders i ncreased in 5 patients and decreased in the other 5 in the second week . The pharmacokinetics of cyclosporin differed in the 2 groups: in pat ients without severe hepatic disorders, the blood metabolites/cyclospo rin ratio (M/C) stabilised at 1.2 +/- 0.4 in week 2 and at 0.8 +/- 0.2 in week 3, bile cyclosporin/blood cyclosporin (bile C/blood C) fluctu ated around 13.5 (13.5 +/- 9.5 in week 2 and 13.5 +/- 9.0 in week 3) a nd the bile metabolite/blood metabolite (bile M/blood M) ratio was ver y high and variable (131 +/- 86 in week 2 and 159 +/- 116 in week 3). Metabolites significantly accumulated in the blood of patients with se vere hepatic disorders (M/C = 2.8 +/- 0.6 in week 2 and 3.5 +/- 1.0 in week 3); bile C/blood C (2.6 +/- 2.1 in week 2 and 3.4 +/- 1.1 in wee k 3) and bile M/blood M (11.9 +/- 7.8 in week 2 and 12.5 +/- 7.9 in we ek 3) significantly decreased and showed less interindividual variabil ity. Blood cyclosporin is usually monitored to help optimise the dosag e. However, if this was extended to include the monitoring of metaboli tes in the blood, and cyclosporin and metabolites in the bile, it coul d provide an early indication of severe hepatic disorders in patients with transplanted livers.