RT Journal Article SR Electronic T1 Development of a Carbon-14 Labeling Approach to Support Disposition Studies with a Pegylated Biologic JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1677 OP 1685 DO 10.1124/dmd.112.044792 VO 40 IS 9 A1 Haiqing Wang A1 Lifei Wang A1 Kai Cao A1 Stuart L. Emanuel A1 Paul Morin A1 Zheng Lin A1 Guoxiang Shen A1 Jennifer Hosbach A1 Donglu Zhang A1 Samuel Bonacorsi A1 A. David Rodrigues A1 Zheng Yang YR 2012 UL http://dmd.aspetjournals.org/content/40/9/1677.abstract AB Although it is widely accepted that one can extend the pharmacokinetic half-life of a therapeutic protein by covalent conjugation with polyethylene glycol (PEG), the disposition properties of such biologics have not yet been fully evaluated. Therefore, a novel [14C]-labeling method was developed that can be applied to a biologic conjugated with PEG through a maleimide-cysteine reaction. The method was used to study the tissue and tumor distribution of a PEGylated Adnectin, a recombinant protein derived from the 10th type III domain of fibronectin, in nude mice bearing human xenograft tumors. The PEGylated Adnectin contained a 40-kDa branched PEG (P40B) that was labeled with [14C] at the linker region between the PEG and Adnectin, without compromising cellular activity and plasma half-life in mice. After a single intravenous or intraperitoneal dose (33 mg/kg, 1.7 μCi per mouse) of [14C]-P40B-Adnectin, quantitative whole-body autoradiography analysis revealed that the liver had the highest uptake of the radioactivity among nontumor tissues, followed by the kidneys and lung. The muscle and brain showed the least penetration of the radioactivity among all tissues examined. In addition, the [14C]-P40B-EI-tandem penetrated into the tumor tissue, although the extent of accumulation was largely dependent on tumor type. Therefore, it was possible to assess the tissue distribution of a PEGylated biologic after it had been [14C] labeled using the novel method described herein.