Cholestasis and kidney dysfunction in liver transplant patients reduces cyclosporine metabolite excretion

Cyclosporin A (CsA) is metabolized principally by the hepatic cytochrome P 450-dependent microsomal enzyme system and eliminated virtually entirely as metabolites, mainly in the bile. Only less than 1% of the oral dose is excreted unmetabolized in the urine or bile. Metabolites account for 50-70% of the total CsA in whole blood. Some of the metabolites have been shown to possess an immunosuppressive and even toxic effect but the role of this effect remains uncertain. In order to evaluate the effect of liver and kidney failure on the metabolism of CsA, we studied twelve patients who had undergone liver transplantation. The samples were collected during the first 4 postoperative weeks. The aim of the study was threefold: to evaluate (1) whether an impairment of liver function, as measured by standard biochemical liver function tests, decreased the metabolism or excretion of CsA; (2) whether an induction of either the CsA metabolites or the parent compound took place in the first postoperative period; and (3) whether kidney failure, as measured by serum creatinine, correlated with blood levels of CsA or its metabolites.