Nasal Absorption and Pharmacokinetic Disposition of Salmon Calcitonin Modified with Low Molecular Weight Polyethylene Glycol

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This study was performed to examine the absorption potential of polyethylene glycol (PEG)-modified salmon calcitonin (sCT) in rats administered via the nasal route. Previous studies have used relatively high molecular weight polyethylene glycols (e.g., ≥ 5000 daltons) for PEG-modification of sCT to provide increased metabolic stability and biological half-life. Unlike these studies, the present study utilized a low molecular weight succinimidyl-propionated monomethoxy-poly(ethylene glycol) (MW 2000). It was hypothesized that the potential for membrane transport would not be significantly altered due to a relatively small increase in the molecular size while the metabolic stability would be enhanced due to resistance to proteolytic degradation. After PEG-modification of sCT, the mono-PEG positional isomer (mono-PEG_<2K>-sCT) was separated from di-PEG_<2K>-sCT, tri-PEG_<2K>-sCT, and unmodified sCT by size exclusion chromatography. The mono-PEG_<2K>-sCT and unmodified sCT were radioiodinated, and the resulting ^<125>I-sCT and ^<125>I-mono-PEG_<2K>-sCT were separated from free iodine by RP HPLC and confirmed by MALDI-TOF MS. The ^<125>I-sCT and ^<125>I-mono-PEG_<2K>-sCT were administered to rats via the nasal route, and serial blood, tissue, and urine samples were taken for up to 36 h for the determination of radioactivity. Mono-PEG_<2K>-sCT exhibited significantly increased AUC (20638 vs. 3650 ng・min/ml), t_<max> (520 vs. 77 min), and t<1/2,λz> (923 vs. 199 min) compared with unmodified sCT. This study demonstrates that mono-PEG_<2K>-sCT is absorbed systemically when given by the intranasal route, exhibiting altered absorption kinetics compared with unmodified sCT.
公益社団法人日本薬学会の論文
2004-08-01

Nasal Absorption and Pharmacokinetic Disposition of Salmon Calcitonin Modified with Low Molecular Weight Polyethylene Glycol

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