Disposition and pharmacokinetics of a polymeric prodrug of mitomycin C, mitomycin C-dextran conjugate, in the rat

Abstract

The disposition and pharmacokinetics of a polymeric prodrug of mitomycin C (MMC), mitomycin C-dextran conjugate (MMCD), following iv bolus administration was studied in rats. Three types of MMCD, conjugates with dextran of molecular weights of 10,000, 70,000, and 500,000, were tested and disposition of carrier dextran and MMC was determined by 14C radioactivity counting and bioassay, respectively. Radioactivity was accumulated in the reticuloendothelial system such as the liver, spleen, and lymph nodes after injection of all three types of 14C-MMCD, but not in the lung, heart, and muscle. Renal distribution of 14C-MMCD varied with the molecular size of the carrier. After injection of cold MMCD, plasma concentrations of MMC in the free and conjugated forms were determined separately on the bases of bioassay. Similar sustained plasma levels of MMC were detected regardless of the carrier size although the concentration-time profiles of MMCD varied with the size of dextran. These plasma concentration data were fitted to a compartment model including a first order conversion process from MMCD to MMC in the central and peripheral compartments of MMCD. Kinetical analysis revealed that MMCD acts as a reservoir of MMC which behaves characteristically as a macromolecule while supplying active MMC in the body.