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Genetically modified mouse models for oral drug absorption and disposition

Seng Chuan Tang1, Jeroen J M A Hendrikx, Jos H Beijnen

  • 1Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Current Opinion in Pharmacology
|September 12, 2013
PubMed

Insights

Drug transporters significantly impact oral drug absorption. Multidrug resistance-associated protein 2 (Mrp2) limits absorption, while Equilibrative nucleoside transporter 1 (Ent1) and others facilitate it, influencing therapeutic efficacy.

Area of Science:

  • Pharmacology and Drug Metabolism
  • Gastrointestinal Physiology
  • Molecular Biology

Background:

  • Oral drug administration relies heavily on intestinal absorption.
  • Enterocyte transmembrane transporters play a crucial role in mediating drug uptake and efflux.
  • Understanding these transporters is key to optimizing oral drug bioavailability and efficacy.

Purpose of the Study:

  • To investigate the role of various drug transporters in intestinal drug absorption.
  • To analyze data from knockout mouse models to elucidate transporter functions in vivo.
  • To identify specific transporters that limit or facilitate the absorption of orally administered drugs.

Main Methods:

  • Review and analysis of studies utilizing knockout mouse models for drug transporters.
  • Examination of in vivo and in vitro data related to drug transport across the intestinal epithelium.
  • Focus on transporters such as Mrp2, Octn1, Octn2, Ent1, Mrp3, Mrp4, Oct1, Oct2, and Oatp.

Main Results:

  • Multidrug resistance-associated protein 2 (Mrp2) was found to limit intestinal drug absorption.
  • Equilibrative nucleoside transporter 1 (Ent1), Mrp3, and potentially Mrp4 facilitate intestinal drug uptake.
  • Organic cation transporter n1 (Octn1) and Octn2 may facilitate absorption, but direct in vivo evidence is limited; Oct1, Oct2, Oatp 1a, and 1b showed no significant role.

Conclusions:

  • Specific drug transporters differentially regulate intestinal drug absorption.
  • Mrp2 acts as a barrier, while Ent1, Mrp3, and Mrp4 promote drug absorption.
  • Further research is needed to confirm the in vivo roles of Octn1 and Octn2 in intestinal drug absorption.

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