Intranasal delivery of PEGylated salmon calcitonins: hypocalcemic effects in rats

Calcif Tissue Int. 2003 Dec;73(6):545-9. doi: 10.1007/s00223-002-0034-9. Epub 2003 Sep 29.

Abstract

To evaluate the hypocalcemic effect of polyethylene gtycol-conjugated salmon calcitonins (PEG-sCT) in rats, mono-PEGylated sCTs (mono-PEG-sCTs) and unmodified sCT were administered via the intranasal route and serum calcium levels were measured by colorimetric assay using o-cresolphthalein. Mono-PEG-sCTs were prepared with different sizes of succinimidyl succinate monomethoxy PEG molecules (PEG2K), PEG5K, PEG12K) and characterized by HPLC and MALDI-TOF mass spectrometry. Nasal instillation of mono-PEG2K-sCT at a dose of 2 IU/kg resulted in sustained reduction in serum calcium levels over 8 hr, with a maximum reduction (% maxd) of 13% after 6 hr of application. Whereas unmodified sCT showed a transient decrease in serum calcium levels with the maximum reduction (5%) observed after 30 min of administration. The overall reductions in serum calcium levels expressed as the net change in AUC relative to control in 8 hr were 11.9 +/- 0.2, 4.6 +/- 0.7, and 2.6 +/- 0.7% for mono-PEG2K-, mono-PEG5K-, and mono-PEG12K-sCT, respectively, compared to 3.2 +/- 0.6% for unmodified sCT. The relative bioavailability of nasally administered 2 IU/kg of mono-PEG2K-sCT was approximately 4-fold higher than nasally administrated unmodified sCT, and the absolute bioavailability was approximately 91% of intravenously injected sCT in 8 hr. It can be concluded that the intranasal absorption of mono-PEG-sCTs was inversely related to the molecular weights of the PEG attached. Of the PEGylated sCTs examined, mono-PEG2K-sCT showed the most pronounced hypocalcemic effect. Therefore the intranasal application would probably be an alternative route of administration for mono-PEG-sCTs in achieving sustained calcium-lowering effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intranasal
  • Animals
  • Area Under Curve
  • Biological Availability
  • Calcitonin / administration & dosage*
  • Calcitonin / chemistry
  • Calcitonin / pharmacokinetics
  • Calcium / blood
  • Chromatography, High Pressure Liquid
  • Hypocalcemia / blood
  • Hypocalcemia / chemically induced*
  • Male
  • Molecular Weight
  • Polyethylene Glycols / administration & dosage*
  • Polyethylene Glycols / chemistry
  • Polyethylene Glycols / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Substances

  • Polyethylene Glycols
  • salmon calcitonin
  • Calcitonin
  • Calcium