METABOLISM OF CYCLOSPORINE AFTER ORTHOTOPIC LIVER-TRANSPLANTATION

The aim of this work was to determine whether the extensive metabolism of cyclosporine, acquired in a donor by treatment with an inducer of cytochrome P450 3A (P450 3A) (cyclosporine oxidase), was transmissible to the recipient by orthotopic liver transplantation. For this purpos e, male Wistar rats were divided into five groups including: control a nimals (group C), animals treated with dexamethasone (an inducer of P4 50 3A, 50 or 300 mg/kg/day, for 4 days, group D), animals transplanted with the livers of control rats (group G) or with the livers of dexam ethasone-induced rats (group GD), and animals treated with beta-naphth oflavone (an inducer of P450 1A, group B). All animals received a sing le i.v. dose of 10 mg/kg cyclosporine 24 hr after either the last dose of inducer or the transplantation. For each group of animals, the are a under the curve (AUC) of cyclosporine was calculated from the curves of blood cyclosporine levels (by radioimmunoassay) against time; live r microsomes were assayed for cyclosporine oxidase activity by HPLC, e rythromycin demethylase and P450 3A level by western blot with specifi c anti-P450 3A antibodies. The decrease in the AUC in groups D and GD with respect to C and G was correlated with increased level of P450 3A (4-5-fold with respect to control) as well as of microsomal cyclospor ine oxidase. In addition, cyclosporine oxidase activity of liver micro somes was specifically inhibited by anti-P450 3A antibodies and trolea ndomycin. The animals in group B did not exhibit increased metabolism of cyclosporine either in vivo or in vitro. We conclude that: (1) cycl osporine is predominantly oxidized in the rat liver by a form of P450 from the 3A subfamily; (2) the extensive metabolism of cyclosporine ac quired by donor rats after treatment with dexamethasone is transmissib le to the recipients through orthotopic liver transplantation.