Regional absorption of fexofenadine<br />Li liang<br />2011.5.17<br />
                                  Contents<br />1. Introduction<br />2. Materials and methods<br />3. Results<br />4. Disc...
                               Introduction<br />Drug absorption depend on :<br /><ul><li>drug’s solubility
  charge
  degradation or metabolization  in GI lumen and gun
  its interaction with export proteins</li></li></ul><li>            Export proteins or efflux transporters<br />Influence...
         Efflux transporters of ABC superfamily<br /><ul><li>Most important members
P-glycoprotein (Pgp)
Multi drug resistance protein 2 (Mrp2)
Breast cancer resistance protein (Bcrp)
Extrusion
Diverse drug
Drug conjugates
Metabolites back into the gun lumen
Sucessful drug’s absorption not affected by ABC transporters</li></li></ul><li>
                     Materials and methods<br />
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Reginal absorbtion of fexofenadin

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Reginal absorbtion of fexofenadin

  1. 1. Regional absorption of fexofenadine<br />Li liang<br />2011.5.17<br />
  2. 2. Contents<br />1. Introduction<br />2. Materials and methods<br />3. Results<br />4. Discussion<br />
  3. 3. Introduction<br />Drug absorption depend on :<br /><ul><li>drug’s solubility
  4. 4. charge
  5. 5. degradation or metabolization in GI lumen and gun
  6. 6. its interaction with export proteins</li></li></ul><li> Export proteins or efflux transporters<br />Influence drug bioavailability<br />Limit permeation<br />Expression and located <br />Apical membrance of enterocytes <br />Liver<br />Kidney <br />Bloodbrain barrier and other barrier tissues<br />
  7. 7. Efflux transporters of ABC superfamily<br /><ul><li>Most important members
  8. 8. P-glycoprotein (Pgp)
  9. 9. Multi drug resistance protein 2 (Mrp2)
  10. 10. Breast cancer resistance protein (Bcrp)
  11. 11. Extrusion
  12. 12. Diverse drug
  13. 13. Drug conjugates
  14. 14. Metabolites back into the gun lumen
  15. 15. Sucessful drug’s absorption not affected by ABC transporters</li></li></ul><li>
  16. 16. Materials and methods<br />
  17. 17. In situ absorption study<br />
  18. 18. Sample analysis<br />LC/MS/MS analysis with TIS pos MS-MS detection <br />determine Fexofenadine and antipyrineconcentrations<br />Western blot analysis<br />Western blot analysis for the detection of P-gp<br />Use villin as the reference protein<br />Quantitative real-time RT-PCR (qRT-PCR)<br />RT-PCR for the quantification of oatp1a5 and oatp2b1 mRNA <br />in duodenum , jejunum , ileum and colon in male Wistarrats<br />
  19. 19. Results<br />Fig.1 Comparison of fexofenadine serum AUCs0–90 min (mean±SD)<br />
  20. 20. Pgp protein expression in perfused intestinal segments<br />Fig.2.Relative Pgp protein expression (mean±SD) in the mucosa of the perfused intestinal proximal (n = 4) and distal(n = 3) segments<br />
  21. 21. mRNA expression in different intestinal segments<br />Fig.3. Ethidium bromide stain of PCR products of rat oatp1a5, oatp2b1 and villin in duodenum , jejunum , ileum and colon<br />
  22. 22. Fig. 4. Expression of rat oatp1a5 and oatp2b1 mRNA(mean±SEM) in the mucosa of duodenum , jejunum, ileum and colon of male rats(n = 5 for oatp1a5 and n=9 for oatp2b1). Quantitative real-time PCR was performed as described in Section 2. Expression intensities of duodenum were individually set to 1 and the intensities of jejunum, ileum and colon relative to it. ***Indicate statistical differences of oatp expression in mucosal samples of duodenum and each jejunum, ileum and colon, respectively, with P≤0.01.<br />
  23. 23. Discussion<br />Regional differences in fexofenadine absorption were abrogated in the presence of PSC-833; pgp is responsible for a reduced absorption of fexofenadine in distal small intestine.<br />In vivo relevance of intestinal Pgp expression for the absorption of drugs that are substrates of Pgp.<br />The level of Pgp expression was inversely related to the amount of pgp substrate absorbed across the intestinal epithelium.<br />Both oatp1a5 and oatp2b1 mRNA expression increased along the small intestine .<br />
  24. 24. Conclusion<br />Species-specific difference intestinal absorption of fexofenadine with a more pronounced influence of Pgp-mediated secretion on the drug’s absorption in rats.<br />
  25. 25. Thank you<br />

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