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 purpose, male Wistar rats were divided into five groups including: control animals (group C), animals treated with dexamethasone (an inducer of P450 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 dexamethasone-induced rats (group GD), and animals treated with beta-naphthoflavone (an inducer of P450 1A, group B). All animals received a single 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 area under the curve (AUC) of cyclosporine was calculated from the curves of blood cyclosporine levels (by radioimmunoassay) against time; liver microsomes were assayed for cyclosporine oxidase activity by HPLC, erythromycin demethylase and P450 3A level by western blot with specific 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 cyclosporine oxidase. In addition, cyclosporine oxidase activity of liver microsomes was specifically inhibited by anti-P450 3A antibodies and troleandomycin. The animals in group B did not exhibit increased metabolism of cyclosporine either in vivo or in vitro. We conclude that: (1) cyclosporine is predominantly oxidized in the rat liver by a form of P450 from the 3A subfamily; (2) the extensive metabolism of cyclosporine acquired by donor rats after treatment with dexamethasone is transmissible to the recipients through orthotopic liver transplantation.
Fabre
J M
JM
Service de Chirurgie Digestive C, Hospital Saint Eloi, Montpellier, France.
Pedrosa
R
R
Bonardet
A
A
Pichard
L
L
Descomps
B
B
Domergue
J
J
Baumel
H
H
Maurel
P
P
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001571:Benzoflavones / Q000494:pharmacology; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction; D015151:Immunoblotting; D016031:Liver Transplantation; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D014019:Tissue Donors; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D065607:Cytochrome P-450 Enzyme Inhibitors; D019324:beta-Naphthoflavone; D003907:Dexamethasone; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating