The accumulation mechanism of cationic mitomycin C-dextran conjugates in the liver: in-vivo cellular localization and in-vitro interaction with hepatocytes.
To elucidate the mechanism of the accumulation of mitomycin C-dextran conjugate (MMC-D) in the liver, in-vivo cellular uptake and in-vitro cellular interaction of MMC-D have been studied. Localization of cationic and anionic MMC-D (MMC-Dcat. and MMC-Dan.) in different liver cell types following i.v. administration was examined in rats and the significant contribution of parenchymal cells demonstrated. In-vitro cellular interaction was determined by measuring the drug concentration in the medium after incubation with rat isolated hepatocytes. MMC-Dcat. was highly adsorbed on the surface of hepatocytes at pH 7.2, while the interaction between MMC-Dan. and hepatocytes was negligible. The percentage association of MMC-Dcat. with hepatocytes remained almost constant during the course of incubation and no significant difference was observed between the incubation at 4 and 37 degrees C. The adsorption phenomenon was shown to conform to Langmuir's adsorption isotherm. The amount of MMC-Dcat. associated with hepatocytes increased as the molecular weight of the dextran chain increased. These results showed that MMC-Dcat. was adsorbed on the surface of hepatocytes by an electrostatic force and this binding was responsible for its remarkable accumulation in the liver in-vivo. Thus some physicochemical properties of the MMC-D conjugates are thought to play an important role in the disposition characteristics of the conjugates.
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003911:Dextrans / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D016685:Mitomycin; D008937:Mitomycins / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D003911:Dextrans; D008937:Mitomycins; C042790:mitomycin C-dextran; D016685:Mitomycin