Abstract
The transport barrier of the epithelia presents one of the major problems limiting the effective use of these tissues as alternate delivery routes for macromolecules such as peptides and proteins. In the present study, two membrane transport properties, namely, the permeability and permselectivity of the shunt pathway, were investigated and compared in various tissues including the nasal, tracheal, bronchial, buccal, rectal, vaginal, corneal, epidermal, duodenal, jejunal, ileal, and colonic epithelia. Membrane permeability was evaluated using a combined method based on electrical conductance and flux measurements of a hydrophilic fluorescent probe, 6-carboxy fluorescein (CF). Membrane permselectivity or the charge discriminating ability of the membrane was evaluated by KCl diffusion potential measurements. The results indicate that all epithelia under investigation possess a relatively high degree of permeation barrier and are highly selective for the absorption of positively charged solutes. Shunt path permeability was found to vary greatly among tissues from different epithelia, whereas membrane charge selectivity was relatively constant in these tissues. A good correlation was observed between membrane electrical conductance and steady-state flux of CF, indicating a paracellular transport of the compound. The rank order of the intrinsic membrane permeability was as follows: intestinal≈ nasal ≥ bronchial ≥ tracheal > vaginal ≥ rectal > corneal > buccal > skin. Membrane permselectivity, expressed as the ratio of transport number (positive over negative), ranges from 1.78 for the buccal to 1.33 for the rectal epithelium. These results suggest that, for effective delivery purposes, permeation enhancing methods, by either increasing tissue permeability or modifying drug-membrane charge selectivity, are generally required. The permeation data also suggest that the respiratory epithelia represent good alternate routes for drug delivery, particularly for those that are orally ineffective, i.e., due to extensive gastrointestinal tract degradation or first-pass metabolism.
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REFERENCES
D. C. Corbo, J. C. Liu, and Y. W. Chien. Characterization of the barrier properties of mucosal membranes. J. Pharm. Sci. 79:202–206 (1990).
B. J. Aungst, N. J. Rogers, and E. Shefter. Comparison of nasal, rectal, sublingual and intramuscular insulin efficiency and the effects of a bile salt absorption promoter. J. Pharmacol. Exp. Ther. 244:23–27 (1987).
E. Fromter and J. Diamond. Route of passive ion permeation in epithelia. Nature New Biol. 53:9–13 (1972).
Y. Rojanasakul and J. R. Robinson. Electrophysiological and ultrastructural characterization of the cornea during in vitro perfusion. Int. J. Pharm. 63:1–16 (1990).
P. H. Barry and J. M. Diamond. Junction potentials, electrode standard potentials and other problems in interpreting electrical properties of membranes. J. Membr. Biol. 3:93–122 (1970).
R. A. Robinson and R. H. Stokes. Electrolytic Solutions, Butterworths, London, 1959.
Y. Rojanasakul and J. R. Robinson. Transport mechanisms of the cornea: Characterization of barrier permselectivity. Int. J. Pharm. 55:237–246 (1989).
L. A. Stoehelin. Structure and function of intercellular junctions. Int. Rev. Cytol. 39:210 (1974).
S. G. Schultz, R. A. Frizzell, and H. N. Nellans. Active sodium transport and the electrophysiology of rabbit colon. J. Membr. Biol. 33:351–384 (1977).
D. W. Powell. Barrier function of epithelia. Am. J. Physiol. 241:G275 (1981).
M. A. Wheatley, J. Dent, E. B. Wheeldon, and P. L. Smith. Nasal drug delivery: An in vitro characterization of transepithelial electrical properties and fluxes in the presence or absence of enhancers. J. Control. Release 8:167–177 (1988).
M. J. Welsh. Electrolyte transport by airway epithelia. Physiol. Rev. 67:1143–1184 (1987).
M. Hayashi, T. Hirasawa, T. Muraoka, M. Shiga, and S. Awazu. Comparison of water influx and seiving coefficient in rat jejunal, rectal, and nasal absorption of antipyrine. Chem. Pharm. Bull. 33:2149–2152 (1985).
A. E. Taylor and K. A. Gaar. Estimation of equivalent pore radii of pulmonary capillary and alveolar membranes. Am. J. Physiol. 218:1133–1140 (1970).
C. McMartin, L. E. F. Huctchinson, R. Hyde, and G. E. Peters. Analysis of structural requirements for the absorption of drugs and macromolecules from the nasal cavity. J. Pharm. Sci. 76:535–540 (1987).
S. Hirai, T. Yashiki, and H. Mima. Mechanisms for the enhancement of the nasal absorption of insulin by surfactants. Int. J. Pharm. 9:173–184 (1981).
R. E. Stratford and V. H. L. Lee. Aminopeptidase activity in homogenates of various absorptive mucosae in the albino rabbit: Implication in peptide delivery. Int. J. Pharm. 30:73–82 (1986).
Y. Rojanasakul, S. W. Paddock, and J. R. Robinson. Confocal laser scanning microscopic examination of transport pathways and barriers of some peptides across the cornea. Int. J. Pharm. 61:163–172 (1990).
Y. Rojanasakul. Mechanistic Studies of Ocular Peptide Absorption and Its Enhancement by Various Penetration Enhancers, Ph.D. dissertation, University of Wisconsin—Madison, 1989.
R. L. Dickinson. Human Sex Anatomy, Williams and Wilkins, Baltimore, MD, 1949, c. 2–3.
R. Scheuplein. Mechanisms of percutaneous absorption II: Transient diffusion and the relative importance of various routes of skin penetration. J. Invest. Dermatol. 45:334 (1967).
F. M. Wigley, J. H. Londono, and S. H. Wood. Insulin across respiratory mucosae by aerosol delivery. Diabetes 20:552–556 (1971).
A. Adjei and J. Garren. Pulmonary delivery of peptide drugs: Effect of particle size on bioavailability of leuprolide acetate in healthy male volunteers. Pharm. Res. 7:565–569 (1990).
J. S. Patton, H. J. Fuchs, and J. A. Moore. Pulmonary delivery of peptide and protein drugs. Proc. 17th Int. Symp. Control. Release Soc. 1990, p. 214.
R. R. Burnette and B. Ongpipattanakul. Characterization of the permselective properties of excised human skin during iontophoresis. J. Pharm. Sci. 76:765–773 (1987).
D. H. Smyth and E. M. Wright. Streaming potentials in the rat small intestine. J Physiol. (London) 182:591–602 (1966).
G. Shutten, H. W. Spier, and G. Schwarz. Handbuch Der Hautund Geschlechtskrankheiten, Vol. I/4B, Springer, Berlin, 1981, pp. 113–147.
A. M. Tonjum. Permeability of horseradish peroxidase in rabbit corneal epithelium. Acta Ophthalmol. 52:650–658 (1974).
Y. Maitani, M. Yoshiharu, and T. Nagai. Influence of molecular weight and charge on nasal absorption of dextran and DEAE-dextran in rabbits. Int. J. Pharm. 49:23–27 (1989).
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Rojanasakul, Y., Wang, LY., Bhat, M. et al. The Transport Barrier of Epithelia: A Comparative Study on Membrane Permeability and Charge Selectivity in the Rabbit. Pharm Res 9, 1029–1034 (1992). https://doi.org/10.1023/A:1015802427428
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DOI: https://doi.org/10.1023/A:1015802427428