Chemical degradation of peptide and protein pharmaceuticals can also be analyzed kinetically in the same manner as for small-molecule drugs. Specifically, chemical degradation of small peptides in aqueous solutions generally conforms to simple first-order kinetics. For example, first-order kinetics have been reported for the hydrolysis in aqueous solution of secretin, which has 27 amino acid residues (Fig. 205).795 Deamidation, hydrolysis, and epimerization of an LH-RH antagonist having 10 amino acid residues (Fig. 206),802 deamidation of calcitonin, having 32 amino acid residues (Fig. 207),876 and degradation of gonadorelin877 and growth hormone-releasing hexapeptide878 also follow first-order kinetics.
Kinetic analysis has even been attempted for the degradation of peptide and protein pharmaceuticals for which the mechanism and pathways are unknown. Apparent inactivation of a-chymotrypsin and bromelain in aqueous solutions was described by monoexponential
decay, apparent first-order kinetics (Fig. 208).879 Apparent inactivation of kallikrein was described according to a kinetic model representing a reversible and an irreversible reaction (Eq. 5.1) or an alternative model representing independent irreversible inactivation of two isoenzymes (Eq. 5.2).879
The kinetics of solid-state degradation of peptide and protein pharmaceuticals is difficult to describe for many of the same reasons that it is difficult to describe solid-state inactivation of small molecules. Apparent inactivation of digestive enzymes such as lipase was analyzed empirically using the Weibull equation (Eq. 2.69), as shown in Fig. 209,880-881 whereas apparent inactivation of dry horse serum cholinesterase was adequately described by a first-order equation even for inactivation in the solid state.882
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