Ciclosporin metabolite pattern in blood and urine of kidney graft patients in relation to liver function

Abstract

Ciclosporin, an immunosuppressant, is metabolized by the liver cytochrome P450 system. Changes in the pattern of its metabolites in blood and urine in patients with disturbed liver function have been studied. Forty seven kidney graft patients receiving 2.9 mg/kg/d ciclosporin b.i.d., and no additional medication that would interfere with ciclosporin metabolism, were allocated to three groups according to liver function: I with normal liver function (n = 19), II with elevated liver enzyme activity or bilirubin concentration in serum (n = 20), and III with cholestasis (n = 8). Ciclosporin and 17 metabolites were determined in blood and 24 h-urine. In blood the trough concentrations of metabolites M19 and M1A were significantly higher in group III than in groups I and II. The total quantity of metabolites excreted in 24 h-urine was significantly different for H230, M4N69 and M1A (group III greater than I = II). Renal excretion of the daily dose of ciclosporin in patients in group I was 2.7%, group II 3% and group III 5.7%. In group III compared to group I the ciclosporin metabolite pattern was shifted to a relatively higher concentration of M19 in blood and of H 230, M19 and M1A in urine. Since high ciclosporin metabolite concentrations appear to be associated with nephrotoxicity, the metabolite pattern in patients with impaired liver function should be monitored.