Cyclosporin metabolism in transplant patients.

The immunosuppressant cyclosporin, a cyclic undecapeptide, is metabolized to more than 30 metabolites. Cytochrome P450IIIA enzymes located in liver and small intestine are responsible for the biotransformation of cyclosporin and its metabolites and are the site of several drug interactions. It is still under discussion, whether the cyclosporin metabolites are involved in the immunosuppressive and/or toxic activities of cyclosporin. While isolated metabolites show not more than 10-20% of the activity of the mother compound in vitro, metabolite combinations have additive and synergistic effects. Isolated metabolites show no toxic effects in rat models while there is an association between metabolite blood concentrations and cyclosporin toxicity in several clinical studies. Possible mechanisms for the toxic effect of cyclosporin metabolites are covalent binding to macromolecules in liver and kidney, alteration of the cytochrome P450 pattern in liver and kidney, increased endothelin production in the kidney and synergistic effects of cyclosporin combinations on mesangial cells. Liver dysfunction leads to an alteration of the metabolite patterns and to increased concentrations of cyclosporin metabolites in blood. In conclusion there is evidence that cyclosporin metabolites may contribute to cyclosporin toxicity and high metabolite blood concentrations in patients should not be tolerated.