Pharmacokinetic disposition of polyethylene glycol-modified salmon calcitonins in rats

This study first reports the pharmacokinetic disposition of polyethylene gl ycol (PEG)-modified salmon calcitonin (sCT) based on the number of attached PEG molecules. PEG-modified sCT was prepared by covalent linkage with succ inimidyl carbonate monomethoxy polyethylene glycol. Mono- and di-PEG-sCTs w ere separated by size exclusion and reverse phase HPLC, and radioiodinated by the chloramine-T method with (NaI)-I-125. I-125-mono-PEG sCT, I-125-di-P EG-sCT and unmodified I-125-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 dis tribution (229.9 vs, 603.1 ml/kg), while mono-PEG-sCT showed a prolonged el imination 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 fo r the unmodified sCT, but all these chemicals were excreted in urine in sma ll quantities (less than or equal to0.6%). There was a tendency toward redu ced accumulation of PEGylated sCTs in tissues, with its reduction being inv ersely proportional to the molecular size, Accumulation of the total radioa ctivity of the unmodified and PEG-modified sCTs was highest in the liver, f ollowed by kidneys, lungs, spleen, heart and thyroid. When expressed per ti ssue gram weight, however, the highest radioactivity was found in the kidne ys. PEGylated sCTs may have greater therapeutic potential via reduced syste mic clearance and prolonged elimination. half-life over unmodified sCT.