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Comparison Between Permeability Coefficients in Rat and Human Jejunum

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Abstract

Purpose. Our main aim is to determine the effective intestinal permeability (Peff) in the rat jejunum in situ for 10 compounds with different absorption mechanisms and a broad range of physico chemical properties, and then compare them with corresponding historical human in vivo Peff values.

Methods. The rat Peff coefficients are determined using an in situ perfusion model in anaesthetized animals. The perfusion flow rate used is 0.2 ml/min, which is 10 times lower than that used in humans. The viability of the method is assessed by testing the physiological function of the rat intestine during perfusions.

Results. The Peff for passively absorbed compounds is on average 3.6 times higher in humans compared to rats (Peff,man = 3.6 · Peff,rat + 0.03·10−4; R^2 = 1.00). Solutes with carrier-mediated absorption deviate from this relationship, which indicates that an absolute scaling of active processes from animal to man is difficult, and therefore needs further investigation. The fraction absorbed of drugs after oral administration in humans (fa) can be estimated from 1 − e−(2·P eff,man ·t res /r·2.8).

Conclusions. Rat and human jejunum Peff estimates of passively absorbed solutes correlate highly, and both can be used with precision to predict in vivo oral absorption in man. The carrier-mediated transport requires scaling between the models, since the transport maximum and/or substrate specificity might differ. Finally, we emphasize the absolute necessity of including marker compounds for continuous monitoring of intestinal viability.

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REFERENCES

  1. U. Fagerholm and H. Lennernäs. Experimental estimation of the effective unstirred water layer thickness in the human jejunum, and its importance in oral drug absorption. Eur. J. Pharm. Sci., 3:247–53 (1995).

    Google Scholar 

  2. A. Walter and J. Gutknecht. Permeability of small nonelectrolytes through lipid bilayer membranes. J. Membrane Biol., 90:207–17 (1986).

    Google Scholar 

  3. J. S. Trier and J. L. Madara. Chapter 35: Functional morphology of the mucosa of the small intestine. In Physiology of the gastrointestinal tract (2nd edition). Ed. L. R. Johnson. Raven Press, New York, 1981, pp. 925–61.

    Google Scholar 

  4. D. C. Taylor, J. Lynch, and D. E. Leahy. Chapter 11: Models for intestinal permeability to drugs. In Drug delivery to the gastrointestinal tract, Ed. J. G. Hardy, S. S. Davis and C. G. Wilson. Chichester, U. K. Ellis Horwood Ltd., 1989, pp. 133–45.

    Google Scholar 

  5. H. Lennernäs, Ö Ahrenstedt, and A-L. Ungell. Intestinal drug absorption during induced net water absorption in man: A mechanistic study using antipyrine, atenolol and enalaprilat. Br. J. Clin. Pharmacol., 37:589–96 (1994).

    Google Scholar 

  6. D. Nilsson, U. Fagerholm, and H. Lennernäs. The influence of net water absorption on the permeability of antipyrine and levodopa in the human jejunum. Pharm. Res., 11:1541–5 (1994).

    Google Scholar 

  7. U. Fagerholm, L. Borgström, Ö Ahrenstedt, and H. Lennernäs. The lack of effect of induced net fluid absorption on the in vivo permeability of terbutaline in the human jejunum. J. Drug Targeting, 3:191–200 (1995).

    Google Scholar 

  8. H. Lennernäs. Does fluid flow across the intestinal mucosa affect quantitative oral drug absorption? Is it time for a reevaluation? Pharm. Res., 12:1573–82 (1995).

    Google Scholar 

  9. M. R. Uhing and R. E. Kimura. Active transport of 3-O-methyl-glucose by the small intestine in chronically catheterized rats. J. Clin. Invest., 95:2799–805 (1995).

    Google Scholar 

  10. J. M. Diamond. News and views: How to be physiological. Nature, 376:117–8 (1995).

    Google Scholar 

  11. H. Lennernäs, Ö Ahrenstedt, R. Hällgren, L. Knutson, M. Ryde, and L. Paalzow Regional jejunal perfusion, a new in vivo approach to study oral drug absorption in man. Pharm. Res., 9:1243–51 (1992).

    Google Scholar 

  12. H. Lennernäs, D. Nilsson, S-M. Aquilonius, Ö. Ahrenstedt, L. Knutson, and L. Paalzow. The effect of L-leucine on the absorption of levodopa, studied by regional jejunal perfusion in man. Br. J. Clin. Pharmacol., 35:243–50 (1993).

    Google Scholar 

  13. H. Lennernäs, L. Knutson, T. Knutson, L. Lesko, T. Salomonson, and G. L. Amidon. Human effective permeability data for atenolol, metoprolol and carbamazepine to be used in the proposed biopharmaceutical classification for IR-products. Pharm. Res., 12:295 (1995).

    Google Scholar 

  14. H. Lennernäs, L. Knutson, T. Knutson, L. Lesko, T. Salomonson, and G. L. Amidon. Human effective permeability data for furosemide, hydrochlortiazide, ketoprofen and naproxen to be used in the proposed biopharmaceutical classification for IR-products. Pharm. Res., 12:396 (1995).

    Google Scholar 

  15. G. L. Amidon, P. J. Sinko, and D. Fleisher. Estimating human oral fraction dose absorbed: A correlation using rat intestinal membrane permeability for passive and carrier-mediated compounds. Pharm. Res., 5:651–4 (1988).

    Google Scholar 

  16. R. Schultz and D. Winne. Relationship between antipyrine absorption and blood flow rate in rat jejunum, ileum and colon. Naunyn-Schm. Arch Pharmacol, 335:97–102 (1987).

    Google Scholar 

  17. I-D. Lee, U. Fagerholm, H. Lennernäs, and G. Amidon. A study of hydrodynamic characteristics in human intestine applying residence time distribution analysis. Urtti Arto Ed. In Symposium on methods to overcome biological barriers in drug delivery. August 26–28, Kuopio University Publications A Pharm. Sci., 10:p73 (1993).

  18. G. L. Amidon, J. Kou, R. L. Elliot, and E. N. Lightfood. Analysis of models for determining intestinal wall permeabilities. J. Pharm. Sci., 69:1369–73 (1980).

    Google Scholar 

  19. M. D. Levitt, J. M. Kneip, and D. G. Levitt. Use of laminar flow and unstirred layer models to predict intestinal absorption in the rat. J. Clin. Invest. 81:1365–9 (1988).

    Google Scholar 

  20. I. Komiya, J. Y. Park, A. Kamani, N. F. H. Ho, and W. I. Higuchi. Quantitative mechanistic studies in simultaneous fluid flow and intestinal absorption using steroids as model solutes. Int. J. Pharmaceutics, 4,249–62 (1980).

    Google Scholar 

  21. P. J. Sinko, G. D. Leesman, and G. L. Amidon. Predicting fraction absorbed in humans using a macroscopic mass balance approach. Pharm. Res., 8:979–88 (1991).

    Google Scholar 

  22. G. L. Amidon, H. Lennernäs, V. Shah, and J. Crison. A theoretical basis for a biopharmaceutical drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res., 12:413–20 (1995).

    Google Scholar 

  23. R. D. Purves. MINIM 3.0. A Macintosh application for non-linear parameter estimation, 1994.

  24. H. Yuasa, K. Matsuda, and J. Watanabe. Influence of anaesthetic regimens on intestinal absorption in rats. Pharm. Res., 10:884–8 (1993).

    Google Scholar 

  25. D. Winne, H. Görig, and U. Müller. Closed rat jejunal segment in situ: role of pre-epithelial diffusion resistance (unstirred layer) in the absorption process and model analysis. Naunyn-Schm. Arch Pharmacol., 335:204–15 (1987).

    Google Scholar 

  26. J. R. Pappenheimer and K. Z. Reiss. Contribution of solvent drag through intercellular junctions to absorption of nutrients by the small intestine of the rat. J. Membrane Biol., 100:123–36 (1987).

    Google Scholar 

  27. U. Fagerholm and H. Lennernäs. Experimental investigation of the effects of transmucosal fluid flow on the jejunal uptake of D2O and hydrophilic compounds in man and rat. Pharm. Res., 12:296 (1995).

    Google Scholar 

  28. Clarke's Isolation and Identification of Drugs, 2nd edition. Ed. A. C. Moffat. The Pharmaceutical Press, London, 1986.

    Google Scholar 

  29. Therapeutic Drugs. Ed. Sir C. Dollery. Churchill Livingstone, New York, 1991.

    Google Scholar 

  30. R. F. Rekker and R. Mannhold. In Calculation of Drug Lipophilicity. VCH Publishers, Weinheim, New York, Basel, Cambridge, 1992.

    Google Scholar 

  31. T. Itoh, R. Magavi, R. L. Casady, T. Nishihata, and J. H. Rytting. A method to predict percutaneous permeability of various compounds: Shed snake skin as a model membrane. Pharm. Res., 7:1302–6 (1990).

    Google Scholar 

  32. A. Sandberg. Extended-release metoprolol. Dissertation thesis, Uppsala, 1994.

  33. P. Artursson and J. Karlsson. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem. Biophys. Res. Comm., 175:880–5 (1991).

    Google Scholar 

  34. Martindale, 27th edition. Ed. A. Wade, The Pharmaceutical Press, London, 1977.

    Google Scholar 

  35. G. Paintaud. Kinetics of drug absorption and influence of absorption rate on pharmacological effect. Dissertation thesis, Stockholm, 1993.

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Fagerholm, U., Johansson, M. & Lennernäs, H. Comparison Between Permeability Coefficients in Rat and Human Jejunum. Pharm Res 13, 1336–1342 (1996). https://doi.org/10.1023/A:1016065715308

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