Pharmaceutical Research

, Volume 6, Issue 9, pp 813–816 | Cite as

Enhanced Bioavailability of Subcutaneously Injected Insulin Coadministered with Collagen in Rats and Humans

  • Ryohei Hori
  • Fusao Komada
  • Seigo Iwakawa
  • Yutaka Seino
  • Katsuhiko Okumura


The present study was undertaken to develop an agent that stabilizes insulin injected subcutaneously. 125I-Porcine insulin with 0.2 U/kg unlabeled porcine insulin was subcutaneously injected with or without collagen in the rat under the depilated skin of the back. At various times, the radioactivity in subcutaneous tissue was assayed for insulin and its metabolites by gel filtration. The degradation and absorption rate constants of insulin at the subcutaneous injection site were estimated according to a one-compartment model. The degradation rate constant of insulin in the presence of collagen at the injection site was less than half of the control rate. The inhibition was confirmed by increases in the immunoreactive insulin plasma levels and the hypoglycemic effect in rats and healthy volunteers. We postulate that collagen prevents insulin from being degraded by inhibiting proteolytic enzymes, mainly collagenase-like peptidase, in subcutaneous tissue.

insulin collagen injection subcutaneous injection bioavailability 


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  1. 1.
    M. Berger, P. A. Halbon, W. A. Muller, R. E. Offord, A. E. Renold, and M. Vranic. Diabetologia 15:133–140 (1978).Google Scholar
  2. 2.
    R. W. Stevenson, T. I. Tsakok, and J. A. Parsons. Diabetologia 18:423–426 (1980).Google Scholar
  3. 3.
    R. Hori, F. Komada, and K. Okumura. J. Pharm. Sci. 72:435–439 (1983).Google Scholar
  4. 4.
    M. Berger, P. A. Halbon, L. Girardier, J. Seydoux, R. E. Offord, and A. E. Renold. Diabetologia 17:97–99 (1979).Google Scholar
  5. 5.
    S. M. O. Guerra and A. E. Kitabchi. J. Clin. Endocrinol. Metab. 42:869–874 (1976).Google Scholar
  6. 6.
    T. Kobayashi, S. Sawano, T. Itho, K. Kosaka, H. Hirayama, and Y. Kasuya. Diabetes 32:331–336 (1983).Google Scholar
  7. 7.
    F. Komada, K. Okumura, and R. Hori. J. Pharmacobio-Dyn. 8:33–40 (1985).Google Scholar
  8. 8.
    A. L. Rubin, K. H. Stenzel, T. Miyata, M. J. White, and M. Dunn. J. Clin. Pharmacol. 13:309–312 (1973).Google Scholar
  9. 9.
    K. H. Stenzel, J. F. Sullivan, T. Miyata, and A. L. Rubin. Trans. Am. Soc. Artif. Intern. Organs 15:114–117 (1969).Google Scholar
  10. 10.
    K. H. Stenzel, T. Miyata, and A. L. Rubin. Annu. Rev. Biophys. Bioeng. 3:231–253 (1974).Google Scholar
  11. 11.
    P. Freychet, J. Roth, and D. M. Neville Jr. Biochem. Biophys. Res. Commun. 43:400–408 (1971).Google Scholar
  12. 12.
    K. Okumura, F. Komada, and R. Hori. J. Pharmacobio-Dyn. 8:25–32 (1985).Google Scholar
  13. 13.
    C. N. Hales and P. J. Randle. Biochem. J. 88:137–146 (1963).Google Scholar
  14. 14.
    A. Hyvärinen and E. A. Nikkilä. Clin. Chim. Acta 7:140–143 (1962).Google Scholar
  15. 15.
    A. Junod, A. E. Lambert, W. Stauffacher, and A. E. Renold. J. Clin. Invest. 48:2129–2139 (1969).Google Scholar
  16. 16.
    R. Hori, Y. Saito, M. Yasuhara, and K. Okumura. J. Pharmacobio-Dyn. 7:910–916 (1984).Google Scholar
  17. 17.
    M. Gibaldi and D. Perrier. In J. Swarbrick (ed.), Drug and the Pharmaceutical Sciences, Vol. I, Pharmacokinetics, Marcel Dekker, New York, 1975, pp. 1–27.Google Scholar
  18. 18.
    T. Nakagawa, Y. Koyanagi, and H. Togawa. SALS, Library Program of the University of Tokyo Computer Center, Tokyo (1975).Google Scholar
  19. 19.
    R. E. Chipkin, W. Kreutner, and W. Billard. Eur. J. Pharmacol. 102:151–154 (1984).Google Scholar
  20. 20.
    B. Malfloy and J. C. Schwartz. Biochem. Biophys. Res. Commun. 106:276–285 (1982).Google Scholar
  21. 21.
    G. Williams, J. C. Pickup, S. Bowcock, E. Cook, and H. Keen. Diabetologia 24:91–94 (1983).Google Scholar
  22. 22.
    M. Berger, H. J. Cüppers, P. A. Halban, and R. E. Offerd. Diabetes 29:81–83 (1983).Google Scholar
  23. 23.
    W. Lorenz, A. Doenicke, K. Messmer, H. J. Reimann, M. Thermann, W. Lahn, J. Berr, A. Schmal, P. Dormann, P. Regenfuss, and H. Hamelmann. Br. J. Anaesth. 48:151–164 (1976).Google Scholar
  24. 24.
    A. Doenicke, B. Grote, and W. Lorenz. Br. J. Anaesth. 49:681–688 (1977).Google Scholar

Copyright information

© Plenum Publishing Corporation 1989

Authors and Affiliations

  • Ryohei Hori
    • 1
  • Fusao Komada
    • 2
  • Seigo Iwakawa
    • 1
  • Yutaka Seino
    • 3
  • Katsuhiko Okumura
    • 1
  1. 1.Department of Pharmacy, Kyoto University Hospital, Faculty of MedicineKyoto UniversityKyotoJapan
  2. 2.Department of Hospital Pharmacy, School of MedicineKobe UniversityKobeJapan
  3. 3.Department of Clinical Nutrition, Kyoto University Hospital, Faculty of MedicineKyoto UniversityKyotoJapan

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