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Segmental-Dependent Drug Absorption and Delivery: The Intestinal Tract

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Part of the Advances in Delivery Science and Technology book series (ADST)

Abstract

The intestinal tract is a long and complex organ, with significantly variable characteristics throughout it. It is broadly divided to several segments: the small intestine, which is subdivided to duodenum, jejunum, and ileum, and the colon. Each segment has its own unique environment. Conditions in each segment are dependent on a multitude of factors. This chapter surveys three such factors: environmental pH values, transporter expression levels, and CYP3A4 expression. Their influence on drug absorption is discussed, and technologies to exploit them for optimization of absorption are reviewed. In conclusion, segment-specific drug absorption and delivery is a highly important research field; a thorough understanding of the determinants of intestinal environment, considering the whole of the human intestine, is crucial for successful targeting of drugs to specific intestinal regions and exploitation of the variable intestinal conditions for better drug delivery and therapeutic effect.

Keywords

  • Drug Metabolize Enzyme
  • CYP3A4 Expression
  • Peptide Transporter
  • Intestinal Perfusion
  • Core Tablet

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Dahan A, Amidon GL (2009) Segmental dependent transport of low permeability compounds along the small intestine due to P-glycoprotein: the role of efflux transport in the oral absorption of BCS class III drugs. Mol Pharm 6(1):19–28

    CAS  PubMed  CrossRef  Google Scholar 

  2. Dahan A, Lennernäs H, Amidon GL (2012) The fraction dose absorbed, in humans, and high jejunal human permeability relationship. Mol Pharm 9(6):1847–1851

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  3. Dahan A, West BT, Amidon GL (2009) Segmental-dependent membrane permeability along the intestine following oral drug administration: evaluation of a triple single-pass intestinal perfusion (TSPIP) approach in the rat. Eur J Pharm Sci 36(2–3):320–329

    CAS  PubMed  CrossRef  Google Scholar 

  4. Dahan A, Amidon GL, Zimmermann EM (2010) Drug targeting strategies for the treatment of inflammatory bowel disease: a mechanistic update. Expert Rev Clin Immunol 6(4):543–550

    CAS  PubMed  CrossRef  Google Scholar 

  5. Washington N, Washington C, Wilson CG (eds) (2003) Physiological pharmaceutics barriers to drug absorption. Taylor & Francis e-Library, London

    Google Scholar 

  6. Fallingborg J et al (1989) pH-profile and regional transit times of the normal gut measured by a radiotelemetry device. Aliment Pharmacol Ther 3(6):605–613

    CAS  PubMed  CrossRef  Google Scholar 

  7. Dahan A, Miller JM, Amidon GL (2009) Prediction of solubility and permeability class membership: provisional BCS classification of the world's top oral drugs. AAPS J 11(4):740–746

    CAS  PubMed  CrossRef  Google Scholar 

  8. CDER/FDA (2000) Guidance for Industry: waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. Center for Drug Evaluation and Research (CDER)

    Google Scholar 

  9. Lennernäs H (2007) Intestinal permeability and its relevance for absorption and elimination. Xenobiotica 37(10–11):1015–1051

    PubMed  CrossRef  Google Scholar 

  10. Lennernas H (2007) Modeling gastrointestinal drug absorption requires more in vivo biopharmaceutical data: experience from in vivo dissolution and permeability studies in humans. Curr Drug Metab 8(7):645–657

    PubMed  CrossRef  Google Scholar 

  11. Regardh CG et al (1974) Pharmacokinetic studies on the selective beta1-receptor antagonist metoprolol in man. J Pharmacokinet Biopharm 2(4):347–364

    CAS  PubMed  CrossRef  Google Scholar 

  12. Jobin G et al (1985) Investigation of drug absorption from the gastrointestinal tract of man. I. Metoprolol in the stomach, duodenum and jejunum. Br J Clin Pharmacol 19(Suppl 2):97S–105S

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  13. Masaoka Y et al (2006) Site of drug absorption after oral administration: assessment of membrane permeability and luminal concentration of drugs in each segment of gastrointestinal tract. Eur J Pharm Sci 29(3–4):240–250

    CAS  PubMed  CrossRef  Google Scholar 

  14. Dahan A et al (2010) High-permeability criterion for BCS classification: segmental/pH dependent permeability considerations. Mol Pharm 7(5):1827–1834

    CAS  PubMed  CrossRef  Google Scholar 

  15. Alt A et al (2004) Biopharmaceutical characterization of sotalol-containing oral immediate release drug products. Eur J Pharm Biopharm 58(1):145–150

    CAS  PubMed  CrossRef  Google Scholar 

  16. Bachmakov I et al (2006) Characterization of beta-adrenoceptor antagonists as substrates and inhibitors of the drug transporter P-glycoprotein. Fundam Clin Pharmacol 20(3):273–282

    CAS  PubMed  CrossRef  Google Scholar 

  17. Yang Y et al (2007) Biopharmaceutics classification of selected beta-blockers: solubility and permeability class membership. Mol Pharm 4(4):608–614

    CAS  PubMed  CrossRef  Google Scholar 

  18. McConnell EL, Fadda HM, Basit AW (2008) Gut instincts: explorations in intestinal physiology and drug delivery. Int J Pharm 364(2):213–226

    CAS  PubMed  CrossRef  Google Scholar 

  19. Wu ZM et al (2012) HP55-coated capsule containing PLGA/RS nanoparticles for oral delivery of insulin. Int J Pharm 425(1–2):1–8

    CAS  PubMed  CrossRef  Google Scholar 

  20. Lai X et al (2008) Evaluation of poly(styrene-alt-maleic anhydride)-ethanol as enteric coating material. Int J Pharm 352(1–2):66–73

    CAS  PubMed  CrossRef  Google Scholar 

  21. He W et al (2009) Design and in vitro/in vivo evaluation of multi-layer film coated pellets for omeprazole. Chem Pharm Bull (Tokyo) 57(2):122–128

    CAS  CrossRef  Google Scholar 

  22. Budde K et al (2010) Enteric-coated mycophenolate sodium. Expert Opin Drug Saf 9(6):981–994

    CAS  PubMed  CrossRef  Google Scholar 

  23. Ibekwe VC et al (2006) An investigation into the in vivo performance variability of pH responsive polymers for ileo-colonic drug delivery using gamma scintigraphy in humans. J Pharm Sci 95(12):2760–2766

    CAS  PubMed  CrossRef  Google Scholar 

  24. Nugent SG et al (2001) Intestinal luminal pH in inflammatory bowel disease: possible determinants and implications for therapy with aminosalicylates and other drugs. Gut 48(4):571–577

    CAS  PubMed  CrossRef  Google Scholar 

  25. Fallingborg J et al (1993) Very low intraluminal colonic pH in patients with active ulcerative colitis. Dig Dis Sci 38(11):1989–1993

    CAS  PubMed  CrossRef  Google Scholar 

  26. Katsuma M et al (2004) Scintigraphic evaluation of a novel colon-targeted delivery system (CODES) in healthy volunteers. J Pharm Sci 93(5):1287–1299

    CAS  PubMed  CrossRef  Google Scholar 

  27. Estudante M et al (2013) Intestinal drug transporters: an overview. Adv Drug Deliv Rev 15;65(10):1340–1356

    Google Scholar 

  28. Keogh JP (2012) Membrane transporters in drug development. Adv Pharmacol 63:1–42

    CAS  PubMed  CrossRef  Google Scholar 

  29. Han HK (2011) Role of transporters in drug interactions. Arch Pharm Res 34(11):1865–1877

    CAS  PubMed  CrossRef  Google Scholar 

  30. Szakacs G et al (2008) The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). Drug Discov Today 13(9–10):379–393

    CAS  PubMed  CrossRef  Google Scholar 

  31. Fredriksson R et al (2008) The solute carrier (SLC) complement of the human genome: phylogenetic classification reveals four major families. FEBS Lett 582(27):3811–3816

    CAS  PubMed  CrossRef  Google Scholar 

  32. Hediger MA et al (2004) The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteins Introduction. Pflugers Arch 447(5):465–468

    CAS  PubMed  CrossRef  Google Scholar 

  33. Cao X et al (2005) Permeability dominates in vivo intestinal absorption of P-gp substrate with high solubility and high permeability. Mol Pharm 2(4):329–340

    CAS  PubMed  CrossRef  Google Scholar 

  34. Giacomini KM et al (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9(3):215–236

    CAS  PubMed  CrossRef  Google Scholar 

  35. Muller F, Fromm MF (2011) Transporter-mediated drug-drug interactions. Pharmacogenomics 12(7):1017–1037

    PubMed  CrossRef  Google Scholar 

  36. Dahan A, Sabit H, Amidon GL (2009) Multiple efflux pumps are involved in the transepithelial transport of colchicine: combined effect of P-gp and MRP2 leads to decreased intestinal absorption throughout the entire small intestine. Drug Metab Dispos 37(10):2028–2036

    CAS  PubMed  CrossRef  Google Scholar 

  37. MacLean C et al (2008) Closing the gaps: a full scan of the intestinal expression of P-glycoprotein, breast cancer resistance protein, and multidrug resistance-associated protein 2 in male and female rats. Drug Metab Dispos 36(7):1249–1254

    CAS  PubMed  CrossRef  Google Scholar 

  38. Chan LM, Lowes S, Hirst BH (2004) The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability. Eur J Pharm Sci 21(1):25–51

    CAS  PubMed  CrossRef  Google Scholar 

  39. Kunta JR, Sinko PJ (2004) Intestinal drug transporters: in vivo function and clinical importance. Curr Drug Metab 5(1):109–124

    CAS  PubMed  CrossRef  Google Scholar 

  40. Mouly S, Paine M (2003) P-glycoprotein increases from proximal to distal regions of human small intestine. Pharm Res 20(10):1595–1599

    CAS  PubMed  CrossRef  Google Scholar 

  41. Thorn M et al (2005) Cytochromes P450 and MDR1 mRNA expression along the human gastrointestinal tract. Br J Clin Pharmacol 60(1):54–60

    PubMed Central  PubMed  CrossRef  Google Scholar 

  42. Friend DR (2004) Drug delivery to the small intestine. Curr Gastroenterol Rep 6(5):371–376

    PubMed  CrossRef  Google Scholar 

  43. Hoffman A et al (2004) Pharmacokinetic and pharmacodynamic aspects of gastroretentive dosage forms. Int J Pharm 277(1–2):141–153

    CAS  PubMed  CrossRef  Google Scholar 

  44. Kagan L, Hoffman A (2008) Systems for region selective drug delivery in the gastrointestinal tract: biopharmaceutical considerations. Expert Opin Drug Deliv 5(6):681–692

    CAS  PubMed  CrossRef  Google Scholar 

  45. Kagan L et al (2010) Role of p-glycoprotein in region-specific gastrointestinal absorption of talinolol in rats. Drug Metab Dispos 38(9):1560–1566

    CAS  PubMed  CrossRef  Google Scholar 

  46. Bittner B et al (2002) Improvement of the bioavailability of colchicine in rats by co-administration of D-alpha-tocopherol polyethylene glycol 1000 succinate and a polyethoxylated derivative of 12-hydroxy-stearic acid. Arzneimittelforschung 52(9):684–688

    CAS  PubMed  Google Scholar 

  47. Adibi SA (2003) Regulation of expression of the intestinal oligopeptide transporter (Pept-1) in health and disease. Am J Physiol Gastrointest Liver Physiol 285(5):G779–G788

    CAS  PubMed  Google Scholar 

  48. Jappar D et al (2010) Significance and regional dependency of peptide transporter (PEPT) 1 in the intestinal permeability of glycylsarcosine: in situ single-pass perfusion studies in wild-type and Pept1 knockout mice. Drug Metab Dispos 38(10):1740–1746

    CAS  PubMed  CrossRef  Google Scholar 

  49. Ingersoll SA et al (2012) The role and pathophysiological relevance of membrane transporter PepT1 in intestinal inflammation and inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 302(5):G484–G492

    CAS  PubMed  CrossRef  Google Scholar 

  50. Dalmasso G et al (2008) PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation. Gastroenterology 134(1):166–178

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  51. Han HK, Amidon GL (2000) Targeted prodrug design to optimize drug delivery. AAPS PharmSci 2(1):E6

    CAS  PubMed  Google Scholar 

  52. Brodin B et al (2002) Transport of peptidomimetic drugs by the intestinal Di/tri-peptide transporter, PepT1. Pharmacol Toxicol 90(6):285–296

    CAS  PubMed  CrossRef  Google Scholar 

  53. Sugiura T, Kato Y, Tsuji A (2006) Role of SLC xenobiotic transporters and their regulatory mechanisms PDZ proteins in drug delivery and disposition. J Control Release 116(2):238–246

    CAS  PubMed  CrossRef  Google Scholar 

  54. Nozawa T et al (2003) Enhanced intestinal absorption of drugs by activation of peptide transporter PEPT1 using proton-releasing polymer. J Pharm Sci 92(11):2208–2216

    CAS  PubMed  CrossRef  Google Scholar 

  55. Dahan A et al (2012) Targeted prodrugs in oral drug delivery: the modern molecular biopharmaceutical approach. Expert Opin Drug Deliv 9(8):1001–1013

    CAS  PubMed  CrossRef  Google Scholar 

  56. Tamai I (2012) Oral drug delivery utilizing intestinal OATP transporters. Adv Drug Deliv Rev 64(6):508–514

    CAS  PubMed  CrossRef  Google Scholar 

  57. Meier Y et al (2007) Regional distribution of solute carrier mRNA expression along the human intestinal tract. Drug Metab Dispos 35(4):590–594

    CAS  PubMed  CrossRef  Google Scholar 

  58. Muntane J (2009) Regulation of drug metabolism and transporters. Curr Drug Metab 10(8):932–945

    CAS  PubMed  CrossRef  Google Scholar 

  59. Watkins PB (1992) Drug metabolism by cytochromes P450 in the liver and small bowel. Gastroenterol Clin North Am 21(3):511–526

    CAS  PubMed  Google Scholar 

  60. von Richter O et al (2004) Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther 75(3):172–183

    CrossRef  Google Scholar 

  61. Zhang QY et al (1999) Characterization of human small intestinal cytochromes P-450. Drug Metab Dispos 27(7):804–809

    CAS  PubMed  Google Scholar 

  62. Boocock DJ et al (2002) Identification of human CYP forms involved in the activation of tamoxifen and irreversible binding to DNA. Carcinogenesis 23(11):1897–1901

    CAS  PubMed  CrossRef  Google Scholar 

  63. Maseneni S et al (2012) Toxicity of clopidogrel and ticlopidine on human myeloid progenitor cells: importance of metabolites. Toxicology 299(2–3):139–145

    CAS  PubMed  CrossRef  Google Scholar 

  64. Basit AW (2005) Advances in colonic drug delivery. Drugs 65(14):1991–2007

    CAS  PubMed  CrossRef  Google Scholar 

  65. Tubic-Grozdanis M et al (2008) Pharmacokinetics of the CYP 3A substrate simvastatin following administration of delayed versus immediate release oral dosage forms. Pharm Res 25(7):1591–1600

    CAS  PubMed  CrossRef  Google Scholar 

  66. Tamura S et al (2002) 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(3):719–729

    CAS  PubMed  CrossRef  Google Scholar 

  67. Tamura S et al (2003) The site-specific transport and metabolism of tacrolimus in rat small intestine. J Pharmacol Exp Ther 306(1):310–316

    CAS  PubMed  CrossRef  Google Scholar 

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Correspondence to Arik Dahan Ph.D. .

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Wolk, O., Dahan, A. (2014). Segmental-Dependent Drug Absorption and Delivery: The Intestinal Tract. In: Domb, A., Khan, W. (eds) Focal Controlled Drug Delivery. Advances in Delivery Science and Technology. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-9434-8_16

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