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P-Glycoprotein Increases from Proximal to Distal Regions of Human Small Intestine

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Abstract

Purpose. The contribution of the efflux transporter P-glycoprotein (P-gp) as a barrier to drug absorption may depend on its level of expression at the site of absorption. Accordingly, the distribution of P-gp was examined along the entire length of the human small intestine.

Methods. Homogenates prepared from mucosal scrapings from every other 30-cm segment of four unrelated human donor small intestines were analyzed for P-gp and the control protein villin by Western blot.

Results. In each donor intestine, relative P-gp expression (P-gp/villin integrated optical density ratio) progressively increased from proximal to distal regions. Among individuals, relative P-gp levels varied 2.1-fold in the duodenal/proximal jejunal region, 1.5- to 2.0-fold in the middle/distal jejunal region, and 1.2- to 1.9-fold in the ileal region. Within-donor variation was somewhat greater, from 1.5- to 3.0-fold.

Conclusions. These results provide further evidence that the site of absorption can represent another source for the interindividual variation in the oral bioavailability of drugs.

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References

  1. K. E. Thummel, K. L. Kunze, and D. D. Shen. Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction. Adv. Drug Deliv. Rev. 27:99-127 (1997).

    Google Scholar 

  2. S. D. Hall, K. E. Thummel, P. B. Watkins, K. S. Lown, L. Z. Benet, M. F. Paine, R. R. Mayo, D. K. Turgeon, D. G. Bailey, R. J. Fontana, and S. A. Wrighton. Molecular and physical mechanisms of first-pass extraction. Drug Metab. Dispos. 27:161-166 (1999).

    Google Scholar 

  3. D. R. Krishna and U. Klotz. Extrahepatic metabolism of drugs in humans. Clin. Pharmacokinet. 26:144-160 (1994).

    Google Scholar 

  4. J. C. Kolars, P. Schmiedlin-Ren, J. D. Schuetz, C. Fang, and P. B. Watkins. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J. Clin. Invest. 90:1871-1878 (1992).

    Google Scholar 

  5. T. Shimada, H. Yamazaki, M. Mimura, Y. Inui, and F. P. Guengerich. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J. Pharmacol. Exper. Ther. 270:414-423 (1994).

    Google Scholar 

  6. M. F. Paine, M. Khalighi, J. M. Fisher, D. D. Shen, K. L. Kunze, C. L. Marsh, J. D. Perkins, and K. E. Thummel. Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. J. Pharmacol. Exper. Ther. 283:1552-1562 (1997).

    Google Scholar 

  7. P. Kuehl, J. Zhang, Y. Lin, J. Lamba, M. Assem, J. Schuetz, P. B. Watkins, A. Daly, S. A. Wrighton, S. D. Hall, P. Maurel, M. Relling, C. Brimer, K. Yasuda, R. Venkataramanan, S. Strom, K. Thummel, M. S. Boguski, and E. Schuetz. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat. Genet. 27:383-391 (2001).

    Google Scholar 

  8. K. E. Thummel and G. R. Wilkinson. In vitro and in vivo drug interactions involving human CYP3A. Annu. Rev. Pharmacol. Toxicol. 38:389-430 (1998).

    Google Scholar 

  9. K. S. Lown, J. C. Kolars, K. E. Thummel, J. L. Barnett, K. L. Kunze, S. A. Wrighton, and P. B. Watkins. Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel. Lack of prediction by the erythromycin breath test. Drug Metab. Dispos. 22:947-955 (1994).

    Google Scholar 

  10. I. de Waziers, P. H. Cugnenc, C. S. Yang, J. P. Leroux, and P. H. Beaune. Cytochrome P 450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues. J. Pharmacol. Exper. Ther. 253:387-394 (1990).

    Google Scholar 

  11. A. Ayrton and P. Morgan. Role of transport proteins in drug absorption, distribution and excretion. Xenobiotica 31:469-497 (2001).

    Google Scholar 

  12. F. Thiebaut, T. Tsuruo, H. Hamada, M. M. Gottesman, I. Pastan, and M. C. Willingham. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc. Natl. Acad. Sci. USA 84:7735-7738 (1987).

    Google Scholar 

  13. Y. Zhang and L. Z. Benet. The gut as a barrier to drug absorption: combined role of cytochrome P450 3A and P-glycoprotein. Clin. Pharmacokinet. 40:159-168 (2001).

    Google Scholar 

  14. P. B. Watkins. Barrier function of CYP3A4 and P-glycoprotein in the small bowel. Adv. Drug Deliv. Rev. 27:161-170 (1997).

    Google Scholar 

  15. K. S. Lown, D. G. Bailey, R. J. Fontana, S. K. Janardan, C. H. Adair, L. A. Fortlage, M. B. Brown, W. Guo, and P. B. Watkins. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J. Clin. Invest. 99:2545-2553 (1997).

    Google Scholar 

  16. D. Dürr, B. Stieger, G. A. Kullak-Ublick, K. M. Rentsch, H. C. Steinert, P. J. Meier, and K. Fattinger. St John's Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clin. Pharmacol. Ther. 68:598-604 (2000).

    Google Scholar 

  17. S. Mouly, K. S. Lown, D. Kornhauser, J. L. Joseph, W. D. Fiske, I. H. Benedek, and P. B. Watkins. Hepatic but not intestinal CYP3A4 displays dose-dependent induction by efavirenz in humans. Clin. Pharmacol. Ther. 72:1-9 (2002).

    Google Scholar 

  18. A. T. Fojo, K. Ueda, D. J. Slamon, D. G. Poplack, M. M. Gottesman, and I. Pastan. Expression of a multidrug-resistance gene in human tumors and tissues. Proc. Natl. Acad. Sci. USA 84:265-269 (1987).

    Google Scholar 

  19. R. H. Stephens, C. A. O'Neill, A. Warhurst, G. L. Carlson, M. Rowland, and G. Warhurst. Kinetic profiling of P-glycoprotein-mediated drug efflux in rat and human intestinal epithelia. J. Pharmacol. Exp. Ther. 296:584-591 (2001).

    Google Scholar 

  20. D. C. Rubin. Small intestine: anatomy and structural anomalies. In T. Yamada (ed.), Textbook of Gastroenterology, Lippincott Williams & Wilkins, Philadelphia, 1999, pp. 1561-1583.

    Google Scholar 

  21. M. F. Paine, L. Y. Leung, H. K. Lim, K. Liao, A. Oganesian, M. Y. Zhang, K. E. Thummel, and P. B. Watkins. Identification of a novel route of extraction of sirolimus in human small intestine: roles of metabolism and secretion. J. Pharmacol. Exp. Ther. 301:174-186 (2002).

    Google Scholar 

  22. P. Schmiedlin-Ren, K. E. Thummel, J. M. Fisher, M. F. Paine, K. S. Lown, and P. B. Watkins. Expression of enzymatically active CYP3A4 by Caco-2 cells grown on extracellular matrix-coated permeable supports in the presence of 1α,25-dihydroxyvitamin D3. Mol. Pharmacol. 51:741-754 (1997).

    Google Scholar 

  23. O. H. Lowry, N. J. Rosebrough, A. L. Farr, and R. J. Randall. Protein measurement with the folin phenol reagent. J. Biol. Chem. 193:265-275 (1951).

    Google Scholar 

  24. H. Glaeser, S. Drescher, H. van der Kuip, C. Behrens, A. Geick, O. Burk, J. Dent, A. Somogyi, O. Von Richter, E. U. Griese, M. Eichelbaum, and M. F. Fromm. Shed human enterocytes as a tool for the study of expression and function of intestinal drug-metabolizing enzymes and transporters. Clin. Pharmacol. Ther. 71:131-140 (2002).

    Google Scholar 

  25. T. Gramatte, R. Oertel, B. Terhaag, and W. Kirch. Direct demonstration of small intestinal secretion and site-dependent absorption of the beta-blocker talinolol in humans. Clin. Pharmacol. Ther. 59:541-549 (1996).

    Google Scholar 

  26. G. Fricker, J. Drewe, J. Huwyler, H. Gutmann, and C. Beglinger. Relevance of p-glycoprotein for the enteral absorption of cyclosporin A: in vitro–in vivo correlation. Br. J. Pharmacol. 118:1841-1847 (1996).

    Google Scholar 

  27. K. S. Lown, R. R. Mayo, A. B. Leichtman, H. L. Hsiao, D. K. Turgeon, P. Schmiedlin-Ren, M. B. Brown, W. Guo, S. J. Rossi, L. Z. Benet, and P. B. Watkins. Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin. Pharmacol. Ther. 62:248-260 (1997).

    Google Scholar 

  28. S. Tamura, A. Ohike, R. Ibuki, G. L. Amidon, and S. Yamashita. Tacrolimus is a class II low-solubility high-permeability drug: the effect of P-glycoprotein efflux on regional permeability of tacrolimus in rats. J. Pharm. Sci. 91:719-729 (2002).

    Google Scholar 

  29. T. W. Synold, I. Dussault, and B. M. Forman. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nature Med. 7:584-590 (2001).

    Google Scholar 

  30. A. Geick, M. Eichelbaum, and O. Burk. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J. Biol. Chem. 276:14581-14587 (2001).

    Google Scholar 

  31. K. E. Thummel, C. Brimer, K. Yasuda, J. Thottassery, T. Senn, Y. Lin, H. Ishizuka, E. Kharasch, J. Schuetz, and E. Schuetz. Transcriptional control of intestinal cytochrome P-4503A by 1α,25-dihydroxy vitamin D3. Mol. Pharmacol. 60:1399-1406 (2001).

    Google Scholar 

  32. H. Spahn-Langguth, G. Baktir, A. Radschuweit, A. Okyar, B. Terhaag, P. Ader, A. Hanafy, and P. Langguth. P-glycoprotein transporters and the gastrointestinal tract: evaluation of the potential in vivo relevance of in vitro data employing talinolol as model compound. Int. J. Clin. Pharmacol. Ther. 36:16-24 (1998).

    Google Scholar 

  33. V. D. Makhey, A. Guo, D. A. Norris, P. Hu, J. Yan, and P. J. Sinko. Characterization of the regional intestinal kinetics of drug efflux in rat and human intestine and in Caco-2 cells. Pharm. Res. 15:1160-1167 (1998).

    Google Scholar 

  34. O. von Richter, B. Greiner, M. F. Fromm, R. Fraser, T. Omari, M. L. Barclay, J. Dent, A. A. Somogyi, and M. Eichelbaum. Determination of in vivo absorption, metabolism, and transport of drugs by the human intestinal wall and liver with a novel perfusion technique. Clin. Pharmacol. Ther. 70:217-227 (2000).

    Google Scholar 

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Authors and Affiliations

  1. Service de Medecine Interne A, Hopital Lariboisiere, 75475, Paris Cedex 10, France

    Stéphane Mouly

  2. General Clinical Research Center and Division of Pharmacotherapy, University of North Carolina, Chapel Hill, North Carolina, 27599, USA

    Mary F. Paine

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  1. Stéphane Mouly
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Correspondence to Mary F. Paine.

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Mouly, S., Paine, M.F. P-Glycoprotein Increases from Proximal to Distal Regions of Human Small Intestine. Pharm Res 20, 1595–1599 (2003). https://doi.org/10.1023/A:1026183200740

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