BIODEGRADABLE MICROSPHERES .17. LYSOSOMAL DEGRADATION OF PRIMAQUINE-PEPTIDE SPACER ARMS

The pharmacological activity of drugs bound to lysosomotropic drug car riers will depend on the rate of release of the drugs from the drug-ca rrier complex. We have now studied the enzymatic release of primaquine (PQ) from two groups of peptide-PQ derivatives by their incubation wi th rat liver lysosomal fraction. The derivatives have the general stru cture NH2-X-Leu-Ala-Y-PQ and are intended to be coupled via their free a-amino group to starch microparticles. In the first group, Y was var ied, being Leu, Tyr, Lys, or Asp, while X was Ala. In the second one, X was varied, being Ala, Tyr, Lys, or Asp, while Y was Leu. Thus, a sy stematic study of the significance of the varying amino acid compositi on of the tetrapeptides, which can serve as spacer arms in the micropa rticle-drug complexes, for the lysosomal release of PQ was possible. I n addition, some epsilon-aminocaproic acid-PQ derivatives, which lack a free alpha-amino group, were incubated. This was done to study the i mportance of enzymes, other than aminopeptidases, during lysosomal deg radation of these derivatives. The pattern and rate of degradation of all PQ derivatives was followed by HPLC analysis. The results obtained show that endopeptidases, as well as mono- and diaminopeptidases, deg rade the derivatives. PQ cannot be cleaved directly from the derivativ es by any carboxypeptidase-like enzyme. Asp peptides are digested slow ly in the lysosomal fraction. The temporal aspects of reactions were q uantitated using a kinetic model, in which first-order rate constants of all the steps of each peptide degradation sequence were estimated s imultaneously.