title: Characterization, efficacy, pharmacokinetics, and biodistribution of 5kDa mPEG modified tetrameric canine uricase variant.
abstract: PEGylated uricase is a promising anti-gout drug, but the only commercially marketed 10kDa mPEG modified porcine-like uricase (Pegloticase) can only be used for intravenous infusion. In this study, tetrameric canine uricase variant was modified by covalent conjugation of all accessible ɛ amino sites of lysine residues with a smaller 5kDa mPEG (mPEG-UHC). The average modification degree and PEGylation homogeneity were evaluated. Approximately 9.4 5 kDa mPEG chains were coupled to each monomeric uricase and the main conjugates contained 7-11 mPEG chains per subunit. mPEG-UHC showed significantly therapeutic or preventive effect on uric acid nephropathy and acute urate arthritis based on three different animal models. The clearance rate from an intravenous injection of mPEG-UHC varied significantly between species, at 2.61 mL/h/kg for rats and 0.21 mL/h/kg for monkeys. The long elimination half-life of mPEG-UHC in non-human primate (191.48 h, intravenous injection) indicated the long-term effects in humans. Moreover, the acceptable bioavailability of mPEG-UHC after subcutaneous administration in monkeys (94.21%) suggested that subcutaneous injection may be regarded as a candidate administration route in clinical trails. Non-specific tissue distribution was observed after administration of (125)I-labeled mPEG-UHC in rats, and elimination by the kidneys into the urine is the primary excretion route.
authors.affiliation: State Key Laboratory of Bioreactor Engineering, Newworld Institute of Biotechnology, East China University of Science and Technology, Shanghai 200237, PR China.
authors.forename: Chun
authors.initials: C
authors.lastname: Zhang
authors.forename: Kai
authors.initials: K
authors.lastname: Fan
authors.forename: Hua
authors.initials: H
authors.lastname: Luo
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Ma
authors.forename: Riyong
authors.initials: R
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Chunlan
authors.initials: C
authors.lastname: Hu
authors.forename: Zhenmin
authors.initials: Z
authors.lastname: Chen
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Min
authors.forename: Dongzhi
authors.initials: D
authors.lastname: Wei
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D002645:Chickens; D004195:Disease Models, Animal; D004285:Dogs; D004337:Drug Carriers; D005260:Female; D006074:Gout Suppressants / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D006207:Half-Life; D000882:Haplorhini; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control*; D008239:Lysine; D008297:Male; D008657:Metabolic Clearance Rate; D008970:Molecular Weight; D011092:Polyethylene Glycols / Q000737:chemistry*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D013678:Technology, Pharmaceutical / Q000379:methods; D014018:Tissue Distribution; D014503:Urate Oxidase / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D014527:Uric Acid
chemical_list: D004337:Drug Carriers; D006074:Gout Suppressants; D011994:Recombinant Proteins; D014527:Uric Acid; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D014503:Urate Oxidase; D008239:Lysine