Abstract
Purpose. Several low molecular weight amino acids have previously been reported to enable the oral delivery of proteins. In the present studies, the effect of H-MAP (hydroxy methyl amino propionic acid) on the pharmacokinetics (PK) and pharmacodynamics (PD) of porcine insulin delivered to the lungs of rats by spray-instillation (SI) has been determined.
Methods. Aliquots (100 μl) of increasing doses of porcine insulin alone (0.26, 1.3, 2.6, 13, and 26 U/kg) or combined with increasing doses of H-MAP (5, 10, 16, and 25 mg/kg), at pH 7.2-7.6 were administered intratracheally to fasted anesthetized rats using a micro spray-instillator. Blood samples were collected from the jugular vein at specified intervals and the plasma concentrations of insulin and glucose were determined. The PK and PD of porcine insulin alone following subcutaneous (SC) administration of increasing doses were also determined.
Results. The PK of insulin administered either by SI to the lungs or SC injection were absorption rate dependent, resulting in post-peak half-lives 10 to 25-fold greater than the reported intravenous elimination half-life (3 min). The relative bioavailability (F') of insulin administered alone by SI varied from 23.8 to 80% for the lowest and highest insulin dose, respectively. Co-administration of H-MAP and insulin to the lungs significantly changed the PK and PD of insulin in a dose dependent fashion. Maximum PK and PD responses were obtained at an H-MAP dose of 16 mg/kg and an insulin dose of 1.3 U/kg. At this combination, the relative bioavailability of insulin was increased more than 2.5 fold, maximum concentration (Cmax) increased 2-fold and the minimum plasma glucose concentration (%MPGC) was reduced more than 2-fold with respect to same dose of insulin alone. A greater total reduction in plasma glucose (%TRPG0→t) was achieved for H-MAP/insulin combination (66 ± 5 %) compared to insulin alone (47 ± 10 %).
Conclusion. H-MAP has potential for increasing the pulmonary bioavailability of insulin administered through the lungs.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
S. Farr, I. Gonda, and V. Licko. Physicochemical and physiological factors influencing the effectiveness of inhaled insulin. In R. N. Dalby, P. R. Byron, and S. J. Farr (eds.), Respiratory Drug Delivery VI. Interpharm Press, Inc, Hilton Head, South Carolina, 1988 pp. 25-33.
E. Mosekilde, K. Jensen, C. Binder, and S. Pramming. Modeling absorption kinetics of subcutaneous injected soluble insulin. J. Pharmacokinet. Biopharm. 17:67-87 (1989).
J. Patton and R. Platz. Aerosol insulin—a brief review. In P. R. Byron, R. N. Dalby, and S. J. Farr (eds), Respiratory Drug Delivery IV. Interpharm Press, Inc., Richmond, Virginia, 1994 pp. 65-74.
K. Okumura, F. Komada, and H. Ryohei. Fate of porcine and human insulin at the subcutaneous injection site. 1. Degradation and absorption of insulin in the rat. J. Pharmacobio-Dyn. 8:25-32 (1985).
F. Wigley, J. Londono, S. Wood, J. Ship, and R. Waldman. Insulin across respiratory mucosae by aerosol delivery. Diabetes 20:552-556 (1971).
R. Elliott, B. Edgar, C. Pilcher, C. Quested, and J. McMaster. Parenteral absorption of insulin from the lung in diabetic children. Aust. Paediatr. J. 23:293-297 (1987).
B. Laube, A. Georgopoulus, and G. Adams. Aerosolized insulin delivered through the lungs is effective in normalizing plasma glucose levels in non-insulin dependent diabetic subjects. J. Biopharm. Sci. 3:163-169 (1991).
H. Yoshida, K. Okumura, R. Hori, T. Anmo, and H. Yamaguchi. Absorption of insulin delivered to rabbit trachea using aerosol dosage form. J. Pharm. Sci. 68:670-671 (1979).
P. Colthorpe, S. Farr, G. Taylor, I. Smith, and D. Wyatt. The pharmacokinetics of pulmonary-delivered insulin: A comparison of intratracheal and aerosol administration to the rabbit. Pharm. Res. 6:764-768 (1992).
K. Okumura, S. Iwakawa, T. Yoshida, T. Seki, and F. Komada. Intratracheal delivery of insulin. Absorption from solution and aerosol by rat lung. Int. J. Pharm. 88:63-73 (1992).
T. Nishihata, J. H. Rytting, T. Higuchi, and L. Caldwell. Enhanced rectal absorption of insulin and heparin in rats in the presence of non-surfactant adjuvants. J. Pharm. Pharmacol. 33: 334-335 (1981).
C. Damge, C. Michael, M. Aprahmian, and P. Couvereur. New approach for oral administration of insulin with polyalkylcyanoacrylate nanocapsules as drug carrier. Diabetes 37:246-251 (1988).
A. Leone-Bay, N. Santiago, D. Achan, K. Chaudhary, F. DeMorin, L. Falzarano, S. Haas, S. Kalbag, D. Kaplan, H. Leipold, C. Lercara, D. O'Toole, T. Rivera, C. Rosado, D. Sarubbi, E. Vuocolo, N. Wang, S. Milstein, and R.A. Baughman. N-Acylated alpha-amino acids as novel oral delivery agents for proteins. J. Med. Chem. 38:4263-4269 (1995).
S. Milstein, H. Leipold, D. Sarubbi, A. Leone-Bay, G. M. Mlynek, J. R. Robinson, M. Kasimova, and E. Freire. Partially unfolded proteins efficiently penetrate cell membranes-implications for oral drug delivery. J. Control. Release 53:259-267 (1998).
A. Leone-Bay, K. Ho, R. Agarwal, R. Baughman, K. Chaudhary, F. DeMorin, L. Genoble, C. McInnes, S. Lercara, S. Milstein, D. O'Toole, D. Sarubbi, B. Variano, and D. Paton. 4-[4-(2-Hydroxybenzoyl)amion]phenyl]-butyric acid as a novel oral delivery agent for recombinant human growth hormone. J. Med. Chem. 39:2571-2578 (1996).
Handbook SU. PK Analyst Software. Micromath Inc. Provo, Utah 1993 pp.192-197.
W. C. Duckworth and F. G. Hamel. Insulin degradation and Insulin degrading enzyme. In L. S. Jefferson and A. D. Cherrington (eds.), Handbook of Physiology. Section 7. The Endocrine System. Vol. II. The endocrine pancreas and regulation of metabolism. Oxford University Press, New York 2001 pp. 177-194.
A. H. Rubenstein and I. Spitz. Role of the kidney in insulin metabolism and excretion. Diabetes 17:161-169 (1968).
M. Takeyama, T. Ishida, N. Kokubu, F. Komada, S. Iwakawa, K. Okumura, and R. Hori. Enhanced bioavailability of subcutaneously injected insulin by pretreatment with ointment containing protease inhibitors. Pharm. Res. 8:60-64 (1991).
F. Komada, S. Iwakawa, N. Yamamoto, H. Sakakibara, and K. Okumura. Intratracheal delivery of peptide and protein agents: Absorption from solution and dry powder by rat lungs. J. Pharm. Sci. 83:863-867 (1994).
C. L. Densmore, J. L. Johnson, and J. C. Waldrep. Deposition and clearance of 99mTc-labeled cationic lipid:plasmid DNA from the lung of a male rat using the Penn-Century Microsprayer. From Product Literature. Penn Century, Philadelphia, Pennsylvania.
F. Liu, D. Kildsig, and A. Mitra. Pulmonary biotransformation of insulin in rat and rabbit. Life Sci. 51:1683-1689 (1992).
K. Verner and G. Schatz. Protein translocation across membranes. Science 241:1307-1313 (1988).
G. Schatz and B. Dobberstein. Common principles of protein translocation across membranes. Science 271:1519-1526 (1996).
J. L. Izzo, A. M. Roncone, D. L. Helton, and M. J. Izzo. Deposition of 131 I proinsulin in the rat. Comparisons with 131I insulin. Diabetes 27:400-410 (1978).
J. C. Sodoyez, F. R. Sodoyez-Goffaux, and Y. M. Morris. 125I-Insulin: Kinetics of interaction with its receptors and rate of degradation in vivo. Am. J. Physiol. 239:E3-E11 (1980).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Suarez, S., Garcia-Contreras, L., Sarubbi, D. et al. Facilitation of Pulmonary Insulin Absorption by H-MAP: Pharmacokinetics and Pharmacodynamics in Rats. Pharm Res 18, 1677–1684 (2001). https://doi.org/10.1023/A:1013362227548
Issue Date:
DOI: https://doi.org/10.1023/A:1013362227548