PRODRUGS OF PEPTIDES .16. ISOCYCLOSPORIN-A AS A POTENTIAL PRODRUG OF CYCLOSPORINE-A

The kinetics of degradation of isocyclosporin A (isoCyA) was studied in aqueous solution at pH 1-10 and in human plasma. At pH > 5 isoCyA was found to undergo a quantitative conversion to cyclosporin A (CyA) via a mechanism involving intramolecular aminolysis of the ester bond by the N-methyl amino group in the peptide. The pH-rate profile obtained for this O,N-acyl migration was accounted for in terms of spontaneous as well as hydroxide ion-catalyzed aminolysis. The half-life of the conversion of isoCyA to CyA was 21.7 h at pH 7.4 and 37-degrees-C and 12.1 h in 80% human plasma at 37-degrees-C. IsoCyA is suggested as a potential prodrug derivative of CyA which may be useful to improve the delivery characteristics of the parent drug.