Hepatic disposition characteristics of electrically charged macromolecules in rat in vivo and in the perfused liver.
The effect of electric charge on the hepatic disposition of macromolecules was studied in the rat. Charged derivatives of dextran (T-70) and bovine serum albumin (BSA), mitomycin C-dextran conjugates (MMC-D), and lactosaminated BSA (Lac-BSA) were employed as model macromolecules. After intravenous injection, cationic macromolecules were rapidly eliminated from plasma because of their extensive hepatic uptake, while anionic and neutral macromolecules were slowly eliminated. Cationic macromolecules were recovered from parenchymal and nonparenchymal hepatic cells at a cellular uptake (per unit cell number) ratio of 1.4-3.2, while that of Lac-BSA was 14. During liver perfusion using a single-pass constant infusion mode, cationic macromolecules were continuously extracted by the liver, with extraction ratios at steady-state (Ess) ranging between 0.03 and 0.54, whereas anionic and neutral macromolecules were almost completely recovered in the outflow at steady state. The Ess for cationized BSA (Cat-BSA) and cationic MMC-Dcat were concentration dependent and decreased at low temperatures and in the presence of colchicine and cytochalasin B. The possible participation of the internalization process in the uptake of cationic macromolecules by hepatocytes was suggested.
Nishida
K
K
Department of Basic Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Mihara
K
K
Takino
T
T
Nakane
S
S
Takakura
Y
Y
Hashida
M
M
Sezaki
H
H
D000818:Animals; D000838:Anions / Q000493:pharmacokinetics; D002412:Cations / Q000493:pharmacokinetics; D003078:Colchicine / Q000494:pharmacology; D003571:Cytochalasin B / Q000494:pharmacology; D003911:Dextrans / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D046911:Macromolecular Substances; D008297:Male; D016685:Mitomycin; D008937:Mitomycins / Q000493:pharmacokinetics; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D012710:Serum Albumin, Bovine / Q000493:pharmacokinetics; D013696:Temperature
D000838:Anions; D002412:Cations; D003911:Dextrans; D046911:Macromolecular Substances; D008937:Mitomycins; C042790:mitomycin C-dextran; D012710:Serum Albumin, Bovine; D003571:Cytochalasin B; D016685:Mitomycin; D003078:Colchicine