Development of a novel polymeric prodrug of mitomycin C, mitomycin C-dextran conjugate with anionic charge. II. Disposition and pharmacokinetics following intravenous and intramuscular administration

Abstract

Disposition and pharmacokinetics of a novel polymeric prodrug of mitomycin C (MMC), mitomycin C-dextran conjugate with anionic charge (MMC-Dan.), following intravenous (i.v.) and intramuscular (i.m.) injection were studied in rats. Three types of MMC-Dan., conjugates with dextran with molecular weights of 10,000, 70,000, and 500,000 were tested. After i.v. injection, MMC-Dan. showed a exceedingly slow plasma clearance of MMC in the conjugated form, and the disappearance rate was decreased as the molecular weight of the conjugate increased. Urinary excretion was also affected by the molecular weight; i.e. the urinary recovery percent of conjugated MMC was decreased with the increase of the molecular weight of the conjugate. These results suggested that MMC-Dan. was retained in the body for a considerably long period. After i.m. injection, MMC-Dan. disappeared from the injection site with biphasic patterns. In an initial phase, conjugates themselves disappeared with rates depending on their molecular sizes, but thereafter they disappeared at almost the same rate. The release of MMC from subsequent absorption was suggested in the injection site. MMC-Dan. was accumulated in the regional lymph node and transferred to thoracic lymph as their sizes increased and decreased, respectively. The relationship between physicochemical properties, such as molecular weight and electric charge, and the pharmacokinetic behaviour of polymeric prodrug in systemic and local administration was discussed, in comparison with mitomycin C-dextran conjugate with cationic charge (MMC-Dcat.).