Biliary excretion of mitomycin C dextran conjugates in relation to physicochemical characteristics of carrier dextran.
Biliary excretion characteristics of polymeric prodrugs of mitomycin C (MMC), mitomycin C-dextran conjugates with cationic or anionic charge (MMC-Dcat, MMC-Dan) and with different molecular weights of dextran (10,000, 70,000, and 500,000) were studied in rat. Following intravenous injection, bile was periodically collected and concentrations of free and dextran-conjugated MMC in it were determined by bioassay. MMC administered as a free form was excreted rapidly into bile and 1.8% of the dose was recovered within 2 h. A small amount of MMC was gradually excreted into bile after administration of all MMC-Ds and total recovery at 8 h was less than 1% of dose. In this case, a major part of excreted MMC was recovered as a conjugated form. MMC-Dcat gave a larger total excretion of MMC than MMC-Dan and excretion was also affected by the molecular weight of carrier dextran. The biliary recovery of MMC-Dcat labeled with 14C at a spacer moiety was significantly higher than that of conjugated MMC determined by bioassay suggesting release and/or inactivation of MMC in MMC-D during the circulation in the body. These results were compared with biliary excretion of model macromolecules with the same molecular weight but different electric charge in order to clarify the effect of electric charge on the biliary excretion of macromolecules. Cationic macromolecules exhibited higher biliary excretion in relation to greater hepatic uptake.
Hashida
M
M
Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Atsumi
R
R
Nishida
K
K
Nakane
S
S
Takakura
Y
Y
Sezaki
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001659:Biliary Tract / Q000378:metabolism*; D002250:Carbon Radioisotopes; D003911:Dextrans / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004337:Drug Carriers; D007275:Injections, Intravenous; D046911:Macromolecular Substances; D008297:Male; D016685:Mitomycin; D008937:Mitomycins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains
D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D003911:Dextrans; D004337:Drug Carriers; D046911:Macromolecular Substances; D008937:Mitomycins; C042790:mitomycin C-dextran; D016685:Mitomycin