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Intranasal Delivery of PEGylated Salmon Calcitonins: Hypocalcemic Effects in Rats

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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.

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Acknowledgements

This work was supported by grant No. 2000-2-21700-001-3 from the Korea Science & Engineering Foundation and partially by the Brain Korea 21 Program of the Ministry of Education.

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Authors and Affiliations

  1. Drug Targeting Laboratory, College of Pharmacy, SungKyunKwan University, Suwon City 440-746, Korea

    K. C. Lee, M. -O. Park, D. H. Na, Y. S. Youn & S. D. Lee

  2. Pharmacokinetics Laboratory, College of Pharmacy, SungKyunKwan University, Suwon City 440-746, Korea

    S. D. Yoo

  3. College of Pharmacy, Wonkwang University, Iksan 570-749, Korea

    H. S. Lee

  4. College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536-0082, USA

    P. P. DeLuca

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  1. K. C. Lee
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  2. M. -O. Park
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Correspondence to K. C. Lee.

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Lee, K., Park, MO., Na, D. et al. Intranasal Delivery of PEGylated Salmon Calcitonins: Hypocalcemic Effects in Rats . Calcif Tissue Int 73, 545–549 (2003). https://doi.org/10.1007/s00223-002-0034-9

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  • DOI: https://doi.org/10.1007/s00223-002-0034-9

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