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  • Title: Degradation kinetics of three gonadorelin analogues: developing a method for calculating epimerization parameters.
    Author: Hoitink MA, Beijnen JH, Boschma MU, Bult A, van der Houwen OA, Wiese G, Underberg WJ.
    Journal: Pharm Res; 1998 Sep; 15(9):1449-55. PubMed ID: 9755899.
    Abstract:
    PURPOSE: To develop a method for calculating epimerisation parameters, find out if the kinetics of the independent reactions can be established, and elucidate primary structure-chemical degradation relationships in the degradation kinetics of three gonadorelin analogues. METHODS: The influences of pH, temperature, and buffer concentration on the degradation of the three gonadorelin analogues buserelin, goserelin, and triptorelin were investigated using RP-HPLC. A method was developed to calculate epimerisation and hydrolysis rate constants independently. RESULTS: Explicit structure-degradation mechanism relations were found in the degradation of all three compounds. The L-serine residue was found to be involved in both a solvent-catalysed backbone hydrolysis and a hydroxyl-catalysed epimerisation whereas, the O-tertiary butyl D-serine residue was only involved in proton-catalysed ether hydrolysis. The kinetics of identical reactions in different analogues were generally comparable. CONCLUSIONS: The degradation of the gonadorelin analogues is located at a relatively small number of chemical residues and prediction of the degradation mechanisms and kinetics of other peptides with similar structural elements appears to be possible.
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