Comparison Between Permeability Coefficients in Rat and Human Jejunum

Overview

Journal Pharm Res

Specialties Pharmacology
Pharmacy

Date 1996 Sep 1

PMID 8893271

Citations 76

Authors

U Fagerholm

M Johansson

H Lennernas

Affiliations

Soon will be listed here.

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 x 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.Peff,man t rex/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

Sinko P, Leesman G, Amidon G . Predicting fraction dose absorbed in humans using a macroscopic mass balance approach. Pharm Res. 1991; 8(8):979-88. DOI: 10.1023/a:1015892621261. View

Artursson P, Karlsson J . Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem Biophys Res Commun. 1991; 175(3):880-5. DOI: 10.1016/0006-291x(91)91647-u. View

Lennernas H, Ahrenstedt O, Ungell A . Intestinal drug absorption during induced net water absorption in man; a mechanistic study using antipyrine, atenolol and enalaprilat. Br J Clin Pharmacol. 1994; 37(6):589-96. PMC: 1364820. DOI: 10.1111/j.1365-2125.1994.tb04309.x. View

Yuasa H, Matsuda K, Watanabe J . Influence of anesthetic regimens on intestinal absorption in rats. Pharm Res. 1993; 10(6):884-8. DOI: 10.1023/a:1018917412696. View

Amidon G, Lennernas H, Shah V, Crison J . A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995; 12(3):413-20. DOI: 10.1023/a:1016212804288. View

Amidon G, Sinko P, Fleisher D . Estimating human oral fraction dose absorbed: a correlation using rat intestinal membrane permeability for passive and carrier-mediated compounds. Pharm Res. 1988; 5(10):651-4. DOI: 10.1023/a:1015927004752. View

Nilsson D, Fagerholm U, Lennernas H . The influence of net water absorption on the permeability of antipyrine and levodopa in the human jejunum. Pharm Res. 1994; 11(11):1540-7. DOI: 10.1023/a:1018941200575. View

Lennernas H . Does fluid flow across the intestinal mucosa affect quantitative oral drug absorption? Is it time for a reevaluation?. Pharm Res. 1995; 12(11):1573-82. DOI: 10.1023/a:1016220428705. View

WINNE D, Gorig H, Muller U . Closed rat jejunal segment in situ: role of pre-epithelial diffusion resistance (unstirred layer) in the absorption process and model analysis. Naunyn Schmiedebergs Arch Pharmacol. 1987; 335(2):204-15. DOI: 10.1007/BF00177725. View

10.

Schulz R, WINNE D . Relationship between antipyrine absorption and blood flow rate in rat jejunum, ileum, and colon. Naunyn Schmiedebergs Arch Pharmacol. 1987; 335(1):97-102. DOI: 10.1007/BF00165043. View

11.

Amidon G, Kou J, Elliott R, Lightfoot E . Analysis of models for determining intestinal wall permeabilities. J Pharm Sci. 1980; 69(12):1369-73. DOI: 10.1002/jps.2600691204. View

12.

Diamond J . Guts. How to be physiological. Nature. 1995; 376(6536):117-8. DOI: 10.1038/376117a0. View

13.

Lennernas H, Nilsson D, Aquilonius S, Ahrenstedt O, Knutson L, Paalzow L . The effect of L-leucine on the absorption of levodopa, studied by regional jejunal perfusion in man. Br J Clin Pharmacol. 1993; 35(3):243-50. PMC: 1381569. DOI: 10.1111/j.1365-2125.1993.tb05691.x. View

14.

Itoh T, Magavi R, Casady R, Nishihata T, Rytting J . A method to predict the percutaneous permeability of various compounds: shed snake skin as a model membrane. Pharm Res. 1990; 7(12):1302-6. DOI: 10.1023/a:1015902308676. View

15.

Levitt M, Kneip J, Levitt D . Use of laminar flow and unstirred layer models to predict intestinal absorption in the rat. J Clin Invest. 1988; 81(5):1365-9. PMC: 442565. DOI: 10.1172/JCI113464. View

16.

Walter A, Gutknecht J . Permeability of small nonelectrolytes through lipid bilayer membranes. J Membr Biol. 1986; 90(3):207-17. DOI: 10.1007/BF01870127. View

17.

PAPPENHEIMER J, Reiss K . Contribution of solvent drag through intercellular junctions to absorption of nutrients by the small intestine of the rat. J Membr Biol. 1987; 100(2):123-36. DOI: 10.1007/BF02209145. View

18.

Uhing M, Kimura R . Active transport of 3-O-methyl-glucose by the small intestine in chronically catheterized rats. J Clin Invest. 1995; 95(6):2799-805. PMC: 295965. DOI: 10.1172/JCI117984. View

19.

Fagerholm U, Borgstrom L, Ahrenstedt O, Lennernas H . The lack of effect of induced net fluid absorption on the in vivo permeability of terbutaline in the human jejunum. J Drug Target. 1995; 3(3):191-200. DOI: 10.3109/10611869509015945. View

20.

Lennernas H, Ahrenstedt O, Hallgren R, Knutson L, RYDE M, Paalzow L . Regional jejunal perfusion, a new in vivo approach to study oral drug absorption in man. Pharm Res. 1992; 9(10):1243-51. DOI: 10.1023/a:1015888813741. View