Hepatic levels of cyclosporine and metabolites in patients after liver transplantation

Despite the critical role of the liver in the metabolism of cyclosporine, only a few studies have measured hepatic levels (CSA(H)) in patients receiving the drug, and none has directly assayed hepatic levels of the metabolites. In this study we measured CSA(H) and its principal metabolites (mono-OH and di-OH CSA) by HPLC/mass spectroscopy in 19 liver biopsy specimens collected from 14 patients who had undergone liver transplantation, in order to determine how they correlated with blood levels (CSA(B)). The hepatic concentrations were also compared with biochemical and histological parameters of cholestasis. A positive correlation was observed between CSA(H) and CSA(B) (r=0.47), irrespective of the length of time the patients had received the drug (7 to 1662 days) as defined by the relationship: CSA(H)(ng/g wet weight) = 6.7 x CSA(B)(ng/ml) + 338. Hepatic levels of metabolites exceeded those of the parent compound in 11 biopsy specimens. No correlation was found for CSA(H) and the metabolites and serum bilirubin or the degree of cholestasis in the liver biopsy specimens. These findings indicate that: (1) CSA is concentrated in liver tissue several-fold over blood; (2) The hepatic concentration can be estimated from the blood concentration even; in the presence of cholestasis; (3) Significant levels of CSA metabolites are found in liver tissue, frequently exceeding the concentration of the parent compound.