Abstract
Purpose: This study was conducted to explore the role of the peripheral lymphatics in insulin absorption following subcutaneous (SC) administration using a sheep model that allows continuous collection of peripheral lymph and simultaneous assessment of systemic bioavailability.
Methods: In a parallel group design, soluble human insulin (0.5 IU/kg) was administered by bolus SC injection into the interdigital space of the hind leg of non-cannulated control sheep, and sheep in which the efferent popliteal lymph duct was cannulated. A separate group received a bolus IV injection (0.15 IU/kg). Blood was sampled from all animals, and lymph was collected continuously over 12 h post-dosing. Samples were assayed for insulin by ELISA.
Results: The SC bioavailability of insulin in control sheep was 31.5 ± 3.2%, which was significantly higher than when the peripheral lymph was continuously collected (18.4 ± 1.7%). In the lymph-cannulated animals, 17.3 ± 1.0% of the dose was collected in peripheral lymph.
Conclusions: Based on the direct measurement of insulin in regional lymph and on the decrease in the systemic bioavailability when regional lymph was continuously collected, the results demonstrate that lymphatic absorption contributed significantly to the overall insulin bioavailability following SC administration to sheep.
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REFERENCES
The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 329:977-986 (1993).
C. Binder. A theoretical model for the absorption of soluble insulin. In: P. Brunetti, K. G. M. M. Alberti, A. M. Albisser, K. D. Hepp, and M. Massi-Benedetti (eds.), Artificial Systems for Insulin Delivery, Raven, New York, 1983, pp. 53-57.
J. Brange, U. Ribel, J. F. Hansen, G. Dodson, M. T. Hansen, S. Havelund, S. G. Melberg, F. Norris, K. Norris, L. Snel, A. R. Sorensen, and H. O. Voigt. Monomeric insulins obtained by protein engineering and their medical implications. Nature 333:679-682 (1988).
S. Kang, J. Brange, A. Burch, A. Volund, and D. R. Owens. Subcutaneous insulin absorption explained by insulin's physicochemical properties. Evidence from absorption studies of soluble human insulin and insulin analogues in humans. Diabetes Care 14:942-948 (1991).
J. Brange, J. F. Hansen, L. Langkjaer, J. Markussen, U. Ribel, and A. R. Sorensen. Insulin analogues with improved absorption characteristics. Horm. Metab. Res. Suppl. 26:125-130 (1992).
J. Brange, D. R. Owens, S. Kang, and A. Volund. Monomeric insulins and their experimental and clinical implications. Diabetes Care 13:923-954 (1990).
P. Hildebrandt. Subcutaneous absorption of insulin in insulin-dependent diabetic patients. Influence of species, physicochemical properties of insulin and physiological factors. Dan. Med. Bull. 38:337-346 (1991).
R. D. DiMarchi, J. P. Mayer, L. Fan, D. N. Brems, B. H. Frank, and L. K. Green. Synthesis of fast-acting insulin based on structural homology with insulin-like growth factor 1. In: J. A. Smith and J. E. Rivier (eds.), Peptides XII (Proceedings of the 12th American Peptide Symposium), Escom, Leiden, 1992, pp. 26-28.
C. Binder. Absorption of injected insulin. A clinical-pharmacological study. Acta Pharmacol. Toxicol. (Copenh.) 2:1-84 (1969).
P. Hildebrandt, L. Sestoft, and S. L. Nielsen. The absorption of subcutaneously injected short-acting soluble insulin: influence of injection technique and concentration. Diabetes Care 6:459-462 (1983).
J. P. Vora, A. Burch, J. R. Peters, and D. R. Owens. Relationship between absorption of radiolabeled soluble insulin, subcutaneous blood flow, and anthropometry. Diabetes Care 15:1484-1493 (1992).
J. A. Galloway, C. T. Spradlin, R. L. Nelson, S. M. Wentworth, J. A. Davidson, and J. L. Swarner. Factors influencing the absorption, serum insulin concentration, and blood glucose responses after injections of regular insulin and various insulin mixtures. Diabetes Care 4:366-376 (1981).
M. Berger, H. J. Cuppers, H. Hegner, V. Jorgens, and P. Berchtold. Absorption kinetics and biologic effects of subcutaneously injected insulin preparations. Diabetes Care 5:77-91 (1982).
E. Fernqvist, B. Linde, J. Ostman, and R. Gunnarsson. Effects of physical exercise on insulin absorption in insulin-dependent diabetics. A comparison between human and porcine insulin. Clin. Physiol. 6:489-497 (1986).
B. Linde. Dissociation of insulin absorption and blood flow during massage of a subcutaneous injection site. Diabetes Care 9:570-574 (1986).
A. Supersaxo, W. Hein, H. Gallati, and H. Steffen. Recombinant human interferon alpha-2a: delivery to lymphoid tissue by selected modes of application. Pharm. Res. 5:472-476 (1988).
A. Supersaxo, W. R. Hein, and H. Steffen. Effect of molecular weight on the lymphatic absorption of water-soluble compounds following subcutaneous administration. Pharm. Res. 7:167-169 (1990).
S. A. Charman, A. M. Segrave, G. A. Edwards, and C. J. H. Porter. Systemic availability and lymphatic transport of human growth hormone administered by subcutaneous injection. J. Pharm. Sci. 89:168-177 (2000).
C. J. Porter and S. A. Charman. Lymphatic transport of proteins after subcutaneous administration. J. Pharm. Sci. 89:297-310 (2000).
C. J. H. Porter, G. A. Edwards, and S. A. Charman. Lymphatic transport of proteins after SC injection: Implications of animal model selection. Adv. Drug Deliv. Rev. 50:157-171 (2001).
V. P. Shah, K. K. Midha, J. W. A. Findlay, H. M. Hill, J. D. Hulse, I. J. McGilveray, G. McKay, K. J. Miller, R. N. Patnaik, M. L. Powell, A. Tonelli, C. T. Viswanathan, and A. Yacobi. Bio-analytical method validation — a revisit with a decade of progress. Pharm. Res. 17:1551-1557 (2000).
A. Plum, H. Agerso, and L. Andersen. Pharmacokinetics of the rapid-acting insulin analog, insulin aspart, in rats, dogs, and pigs, and pharmacodynamics of insulin aspart in pigs. Drug Metab. Dispos. 28:155-160 (2000).
L. Heinemann and J. Woodworth. Pharmacokinetics and gluco-dynamics of insulin lispro. Drugs of Today 34(Suppl. C):23-36 (1998).
J. H. Anderson and V. A. Koivisto. Clinical studies on insulin lispro. Drugs of Today 34(Suppl. C):37-50 (1996).
M. Berger, P. A. Halban, L. Girardier, J. Seydoux, R. E. Offord, and A. E. Renold. Absorption kinetics of subcutaneously injected insulin. Evidence for degradation at the injection site. Diabetologia 17:97-99 (1979).
E. P. Paulsen, J. W. Courtney, and W. C. Duckworth. Insulin resistance caused by massive degradation of subcutaneous insulin. Diabetes 28:640-645 (1979).
E. W. Kraegen and D. J. Chisholm. Pharmacokinetics of insulin. Implications for continuous subcutaneous insulin infusion therapy. Clin. Pharmacokinet. 10:303-314 (1985).
P. Hildebrandt, P. Sejrsen, S. L. Nielsen, K. Birch, and L. Sestoft. Diffusion and polymerization determines the insulin absorption from subcutaneous tissue in diabetic patients. Scand. J. Clin. Lab. Invest. 45:685-690 (1985).
G. W. Schmid-Schonbein. Mechanisms causing initial lymphatics to expand and compress to promote lymph flow. Arch. Histol. Cytol. 53Suppl:107-114 (1990).
K. Aukland and R. K. Reed. Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. Physiol. Rev. 73:1-78 (1993).
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Charman, S.A., McLennan, D.N., Edwards, G.A. et al. Lymphatic Absorption Is a Significant Contributor to the Subcutaneous Bioavailability of Insulin in a Sheep Model. Pharm Res 18, 1620–1626 (2001). https://doi.org/10.1023/A:1013046918190
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DOI: https://doi.org/10.1023/A:1013046918190