Absorption characteristics of macromolecular prodrugs of mitomycin C following intramuscular administration.

Abstract

The absorption characteristics of several kinds of macromolecular compounds following intramuscular injection were studied in rats. Three types of 14C-labeled mitomycin C-dextran conjugates (14C-MMC-D), bare 14C-dextran, 14C-inulin, and 131I-albumin were used, and their absorption and subsequent lymphatic uptake were determined by radioactivity counting. Clearance of cationic 14C-MMC-D from the injection site was slow and varied with the molecular weight. Remarkable accumulation of radioactivity was observed in the regional lymph node after injection of 14C-MMC-D. Bare 14C-dextran showed similar behavior, but the rate of clearance was faster and less accumulation in the lymph node was observed compared with 14C-MMC-D of the same molecular weight. In contrast 14C-inulin and 131I-albumin showed rapid disappearance from the muscle and no accumulation in the lymph node. Muscular absorption data were fitted to a compartment model including a Langmuir-type adsorption. Pharmacokinetic analysis revealed that the rate of absorption and the degree of adsorption depended on the molecular weight and electric charge, and MMC-D with a molecular weight of 500000 proved to have the longest period of residence. Thus, it was elucidated that physicochemical properties, such as molecular weight and electric charge, affect the pharmacokinetic behavior of macromolecular compounds injected topically.