Pharmacokinetic disposition of polyethylene glycol-modified salmon calcitonins in rats

This study first reports the pharmacokinetic disposition of polyethylene glycol (PEG)-modified salmon calcitonin (sCT) based on the number of attached PEG molecules. PEG-modified sCT was prepared by covalent linkage with succinimidyl carbonate monomethoxy polyethylene glycol. Mono- and di-PEG-sCTs were separated by size exclusion and reverse phase HPLC, and radioiodinated by the chloramine-T method with Na125I. 125I-mono-PEG sCT, 125I-di-PEG-sCT and unmodified 125I-sCT were administered to rats by i.v. injection. Serial blood samples, urine and various tissue samples were taken for the determination of radioactivity. Di-PEG-sCT exhibited significantly reduced systemic clearance (2.3 vs. 11.1 ml/min/kg) and steady-state volume of distribution (229.9 vs. 603.1 ml/kg), while mono-PEG-sCT showed a prolonged elimination half-life (189.1 min vs. 59.8 min) compared with unmodified sCT. The extent of urinary excretion of the PEG-modified sCTs was higher than for the unmodified sCT, but all these chemicals were excreted in urine in small quantities (< or = 0.6%). There was a tendency toward reduced accumulation of PEGylated sCTs in tissues, with its reduction being inversely proportional to the molecular size. Accumulation of the total radioactivity of the unmodified and PEG-modified sCTs was highest in the liver, followed by kidneys, lungs, spleen, heart and thyroid. When expressed per tissue gram weight, however, the highest radioactivity was found in the kidneys. PEGylated sCTs may have greater therapeutic potential via reduced systemic clearance and prolonged elimination half-life over unmodified sCT.