Cyclosporine: structure, pharmacokinetics, and therapeutic drug monitoring

Cyclosporine is an 11-amino acid cyclic peptide immunosuppressant that has revolutionized organ transplantation. Alone or in combination with prednisone and azathiaprine, it is preferred in hepatic, cardiac, and high-risk renal transplantation. Its unusual primary structure of hydrophobic, N-methylated amino acids results in a compact conformation in the crystal which changes to multiple conformations in hydrophilic solvents. The unusual structure produces unusual pharmacokinetic behavior which is still poorly understood. The metabolism occurs predominately in the liver and is affected by several drugs known to alter hepatic metabolism. At least ten metabolites have been identified but are inadequately characterized. The unique behavior of cyclosporine necessitates therapeutic drug monitoring (TDM) for individualization of therapy. Cyclosporine has been monitored in both whole blood and plasma by both RIA and HPLC with significantly different results for each combination. When cyclosporine is assayed by HPLC in a compulsive regimen of TDM, a correlation is observed between immunosuppression, toxicity, and concentration. To distinguish renal or hepatic toxicity from rejection, biopsies, clinical status, and blood concentrations of cyclosporine must be simultaneously analyzed. After extensive experimental and clinical study, cyclosporine remains an enigma with clear clinical benefit.