CHARACTERIZATION OF GLUCURONIDATED PHASE-II METABOLITES OF THE IMMUNOSUPPRESSANT CYCLOSPORINE IN URINE OF TRANSPLANT PATIENTS USING TIME-OF-FLIGHT SECONDARY-ION MASS-SPECTROMETRY

The immunosuppressant, cyclosporine, is metabolized in the liver and s mall intestine to >30 metabolites. Metabolism and immunosuppressive an d toxic potentials of the metabolites are still unclarified. Therefore , search and determination of new metabolites remain an important part of cyclosporine research. In this study, cyclosporine metabolites wer e determined in 42 urine samples of transplant patients using time-of- flight secondary-ion MS. Besides the known metabolites of phase I and phase II, other groups of new phase II metabolites were detected, and most of them were identified as glucuronidated phase I metabolites. Al l metabolites were found in the urine of heart, kidney, and bone marro w graft patients, with frequencies in the range of 74% and 12%. The mo st intensive group of these metabolites was also detected in a HPLC fr action, together with the known glucuronidated AM1c. The concentration of this new metabolic group could be estimated to less than or equal to 5/ml. In conclusion, this work demonstrated that time-of-flight sec ondary-ion MS is a powerful tool in pharmacological investigations. Fu rthermore this study showed that phase II metabolism is an important m etabolic pathway of cyclosporine in transplant patients.