Tissue distribution of 111In-labeled uricase conjugated with charged dextrans and polyethylene glycol.
Uricase (UC) was conjugated with dextran, cationic diethylaminoethyl-dextran (DEAED), and anionic carboxymethyl-dextran (CMD) giving a molecular weight of 10000 by the periodate oxidation method. Their disposition characteristics were studied after intravenous injection (i.v.) in mice. Disposition of the conjugate with activated polyethylene glycol (PEG2) with a similar molecular weight was also studied for comparison. Tissue distribution of the 111In-labeled UC in these conjugates was evaluated by a tissue uptake clearance index calculated in terms of clearance. After i.v. injection, 111In-UC was slowly eliminated from the circulation and gradually accumulated in the liver, spleen, and kidney. Conjugation with neutral dextran slightly enhanced the uptake of 111In-UC by the liver and spleen, while PEG2 conjugation decreased the tissue uptake and resulted in extremely long plasma retention. On the other hand, DEAED and CMD conjugation resulted in significant enhancement and reduction of hepatic uptake, respectively. These results demonstrated that the pharmacokinetic behaviour of UC can be widely controlled by chemical modification with macromolecules having adequate physiochemical properties.
Fujita
T
T
Department of Basic Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Yasuda
Y
Y
Takakura
Y
Y
Hashida
M
M
Sezaki
H
H
D000818:Animals; D003911:Dextrans / Q000737:chemistry*; D004560:Electricity; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry*; D014018:Tissue Distribution; D014503:Urate Oxidase / Q000737:chemistry / Q000493:pharmacokinetics*
D003911:Dextrans; D007205:Indium Radioisotopes; D011092:Polyethylene Glycols; D014503:Urate Oxidase