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Surface Activity and Concentration Dependent Intestinal Permeability in the Rat

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Abstract

Purpose. To investigate the relation between intestinal effective permeability (Peff) and surface activity of fluvastatin and verapamil.

Methods. Peff values were determined for fluvastatin, antipyrine and D-glucose following colon perfusions in the rat in situ. The perfusion solutions differed regarding concentrations of fluvastatin (0-2500 μM) and surface tension (58.9-43.7 mN/m). A cellulose derivative, ethyl-(hydroxyethyl) cellulose (EHEC), was added to lower the surface tension of one of the perfusion solutions. The surface tension of perfusion solutions containing R/S-verapamil (8-814 μM) and R/S-verapamil + chlorpromazine (814 μM + 10 mM) were related to the corresponding Peff values from the literature.

Results. The Peff of fluvastatin correlated inversely (r2 = 0.985, p < 0.05) with the surface tension of the perfusion solutions below the critical micelle concentration (CMC, 1 mM). Decreasing the surface tension with EHEC increased the Peff of fluvastatin by 36% (p < 0.001), but not to the extent anticipated from the correlation between the Peff and the surface tension. EHEC also increased the Peff of antipyrine by 49% (p < 0.01) but not for D-glucose. The Peff of R/S-verapamil correlated inversely with the surface tension (r2 = 0.980, p < 0.001).

Conclusions. The ability of fluvastatin to decrease the surface tension at the membrane surface can partly explain the concentration dependent colonic Peff of fluvastatin. This study shows that the surface activity of the drug molecule itself is an important physicochemical factor that should be taken into consideration when evaluating drug absorption studies performed in vitro or in situ.

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REFERENCES

  1. A. Lindahl, R. Sandström, A.-L. Ungell, and H. Lennernäs. Concentration-and region-dependent intestinal permeability of fluvastatin in the rat. J. Pharm. Pharmacol. 50:737–744 (1998).

    Google Scholar 

  2. V. D. Makhey and P. J. Sinko. Regional functional expression of multidrug resistance efflux pumps, Pgp and MRP, in human and rat intestine. Pharm. Res. 14:S–646 (1997).

    Google Scholar 

  3. B. H. Stewart, E. L. Reyner, R. Stern, E. A. Zegarac, R. Boyd, and L. R. Whitfield. Atorvastatin inhibits the P-glycoprotein-mediated secretion of 3H-digoxin in Caco-2 cell monolayers. Pharm. Res. 14:S–671 (1997).

    Google Scholar 

  4. J. Dimitroulakos and H. Yeger. HMG-CoA reductase mediates the biological effects of retinoic acid on human neuroblastoma cells: lovastatin specifically targets P-glycoprotein-expressing cells. Nat. Med. 2:326–33 (1996).

    Google Scholar 

  5. M. Holmberg, C. Sandberg, P. Nygren, and R. Larsson. Effects of lovastatin on a human myeloma cell line: increased sensitivity of a multidrug-resistant subline that expresses the 170 kDa P-glycoprotein. Anticancer Drugs. 5:598–600 (1994).

    Google Scholar 

  6. A. T. Florence. Surfactant interactions with biomembranes and drug absorption. Pure & Appl. Chem. 53:2057–2068 (1981).

    Google Scholar 

  7. E. K. Anderberg, C. Nystrom, and P. Artursson. Epithelial transport of drugs in cell culture. VII: Effects of pharmaceutical surfactant excipients and bile acids on transepithelial permeability in monolayers of human intestinal epithelial (Caco-2) cells. J. Pharm. Sci. 81:879–87 (1992).

    Google Scholar 

  8. B. J. Aungst, H. Saitoh, D. L. Burcham, S.-M. Huang, S. A. Mousa, and M. A. Hussain. Enhancement of the intestinal absorption of peptides and non-peptides. J. Contr. Rel. 41:19–31 (1996).

    Google Scholar 

  9. T. Lindmark, T. Nikkila, and P. Artursson. Mechanisms of absorption enhancement by medium chain fatty acids in intestinal epithelial Caco-2 cell monolayers. J. Pharmacol. Exp. Ther. 275: 958–64 (1995).

    Google Scholar 

  10. T. Lindmark, Y. Kimura, and P. Artursson. Absorption enhancement through intracellular regulation of tight junction permeability by medium chain fatty acids in Caco-2 cells. J. Pharmacol. Exp. Ther. 284:362–9 (1998).

    Google Scholar 

  11. M. Tomita, M. Hayashi, T. Horie, T. Ishizawa, and S. Awazu. Enhancement of colonic drug absorption by the transcellular permeation route. Pharm. Res. 5:786–9 (1988).

    Google Scholar 

  12. M. Shima, K. Yohdoh, M. Yamaguchi, Y. Kimura, S. Adachi, and R. Matsuno. Effects of medium-chain fatty acids and their acylglycerols on the transport of penicillin V across Caco-2 cell monolayers. Biosci. Biotechnol. Biochem. 61:1150–5 (1997).

    Google Scholar 

  13. B. Persson, S. Nilsson, and L.-O. Sundelöf. On the characterization principles of some technically important water-soluble nonionic cellulose derivatives. Part II: Surface tension and interaction with a surfactant. Carbohydr. Polym. 29:119–127 (1996).

    Google Scholar 

  14. P. D. Lundin, B. R. Westrom, N. Pantzar, and B. W. Karlsson. Bidirectional small intestinal permeability changes to differentsized molecules after HCl-induced injury in the rat. Dig. Dis. Sci. 42:677–83 (1997).

    Google Scholar 

  15. R. Sandström, A. Karlsson, and H. Lennernäs. The lack of stereoselective P-glycoprotein mediated transport of R/S-verapamil across the rat jejunum. J. Pharm. Pharmacol. In Press (1998).

  16. H. Toreson and B. M. Eriksson. Determination of fluvastatin enantiomers and the racemate in human blood plasma by liquid chromatography and fluorometric detection. J. Chromatogr. A. 729:13–18 (1996).

    Google Scholar 

  17. H. Lennernäs, Ö. Ahrenstedt, R. Hällgren, L. Knutson, M. Ryde, and L. K. Paalzow. Regional jejunal perfusion, a new in vivo approach to study oral drug absorption in man. Pharm. Res. 9:1243–1251 (1992).

    Google Scholar 

  18. 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. 4:249–262 (1980).

    Google Scholar 

  19. A. T. Florence and D. Attwood, Physicochemical principles of pharmacy, Macmillan, London, 2nd ed., 1993.

    Google Scholar 

  20. P. M. Seeman and H. S. Bialy. The surface activity of tranquilizers. Biochem. Pharmacol. 12:1181–1191 (1963).

    Google Scholar 

  21. G. S. Retzinger, L. Cohen, S. H. Lau, and F. J. Kezdy. Ionization and surface properties of verapamil and several verapamil analogues. J. Pharm. Sci. 75:976–82 (1986).

    Google Scholar 

  22. J. A. Marqusee and K. A. Dill. Solute partitioning into chain molecule interphases: Monolayers, bilayer membranes, and micelles. J. Chem. Phys. 85:434–444 (1986).

    Google Scholar 

  23. D. M. Woodcock, M. E. Linsenmeyer, G. Chojnowski, A. B. Kriegler, V. Nink, L. K. Webster, and W. H. Sawyer. Reversal of multidrug resistance by surfactants. Br. J. Cancer. 66:62–8 (1992).

    Google Scholar 

  24. S. Drori, G. D. Eytan, and Y. G. Assaraf. Potentiation of anticancer-drug cytotoxicity by multidrug-resistance chemosensitizers involves alterations in membrane fluidity leading to increased membrane permeability. Eur. J. Biochem. 228:1020–9 (1995).

    Google Scholar 

  25. A. Helenius and K. Simons. Solubilization of membranes by detergents. Biochim. Biophys. Acta. 415:29–79 (1975).

    Google Scholar 

  26. G. W. Gullikson, W. S. Cline, V. Lorenzsonn, L. Benz, W. A. Olsen, and P. Bass. Effects of anionic surfactants on hamster small intestinal membrane structure and function: relationship to surface activity. Gastroenterology. 73:501–11 (1977).

    Google Scholar 

  27. A. Lindahl, R. Sandström, A.-L. Ungell, B. Abrahamsson, T. W. Knutson, L. Knutson, and H. Lennernäs. Jejunal permeability and hepatic extraction of fluvastatin in humans. Clin. Pharmacol. Ther. 60:493–503 (1996).

    Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy, Biomedical Center, Uppsala University, Box 580, S-751 23, Uppsala, Sweden

    Anders Lindahl & Hans Lennernäs

  2. Department of Pharmaceutical Chemistry, Biomedical Center, Uppsala University, Box 574, S-751 23, Uppsala, Sweden

    Bengt Persson

  3. Pharmacokinetics and Metabolism, Preclinical R&D, Astra Hässle AB, S-431 83, Mölndal, Sweden

    Anna-Lena Ungell

Authors
  1. Anders Lindahl
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  2. Bengt Persson
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  3. Anna-Lena Ungell
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  4. Hans Lennernäs
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Correspondence to Hans Lennernäs.

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Lindahl, A., Persson, B., Ungell, AL. et al. Surface Activity and Concentration Dependent Intestinal Permeability in the Rat. Pharm Res 16, 97–102 (1999). https://doi.org/10.1023/A:1018879014281

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