[Critical analysis of the immunosuppressive activity and of the toxicity of cyclosporine metabolites].
Cyclosporin A (CyA) is intensively metabolized by the hepatic cytochrome P450 III monooxygenases A systems in the human liver. Among about twenty metabolites, only twelve of which have been identified, and found in the blood of treated patients. The major metabolic pathways are hydroxylation and N-demethylation of the various amino-acids of the parent compound. Quantitatively, and although there are some differences depending on whether one refers to the residual concentration or to the Area Under Curve (AUC), major metabolites are always, in decreasing significance, M17, M1, M18, and M21. Metabolite/CyA ratio is subjected to numerous variations from one patient to another which can be explained by pharmacogenetics, but can also be affected by the type of graft, the hepatic performance status, and related treatments. Be that as it may, it is metabolites 17 and 1 which are especially present in the blood in large quantities. In fact, if one considers the relative percentage of metabolites in comparison with CyA, expressed in blood AUC, values of 79, 39, 21 and 15% are noticed for M17, M1, M18, and M21, respectively. These percentage become 170, 65, 16 and 10% if one refers to residual concentration. In the aggregate, these results may be extrapolated to the tissues and it has been shown that, excepting the liver which contains high M17 concentrations, metabolites overall appear in equal or lower levels than CyA. They are widely diffused throughout the tissues and the highest levels are found in the liver and kidneys, then in fats and pancreata.(ABSTRACT TRUNCATED AT 250 WORDS)
Garraffo
R
R
Unité de Pharmacocinétique Clinique, Hôpital Pasteur, Nice.
D000818:Animals; D016572:Cyclosporine / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism*
D007166:Immunosuppressive Agents; D016572:Cyclosporine
Analyse critique de l'activité immunosuppressive et de la toxicité des métabolites de la ciclosporine.