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An Intravital Microscopy-Based Approach to Assess Intestinal Permeability and Epithelial Cell Shedding Performance
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Decreased drug penetration in inflamed tissue related to changed mucosal metabolism in experimental colitis

Yann Pellequer1, Verena Weissenborn, Alf Lamprecht

  • 1Laboratory of Pharmaceutical Engineering, University of Franche-Comté, Besançon, France.

Journal of Pharmaceutical Sciences
|June 2, 2007
PubMed

Insights

Inflammation in inflammatory bowel disease (IBD) alters drug metabolism in gut tissue, potentially impacting treatment effectiveness. Immune cells in inflamed tissue significantly influence these drug metabolism changes.

Area of Science:

  • Pharmacology
  • Gastroenterology
  • Drug Metabolism

Background:

  • Pathophysiological changes in inflammatory bowel disease (IBD) affect mucosal protein expression.
  • Altered protein expression can influence drug concentrations at the site of action, impacting therapeutic success.

Purpose of the Study:

  • To investigate how experimental colitis affects drug penetration and metabolism in mucosal tissue.
  • To assess the role of P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) in altered drug disposition during colitis.

Main Methods:

  • Utilized an experimental colitis rat model with Ussing chambers to quantify intratissue drug concentrations.
  • Compared drug penetration and metabolism in healthy versus inflamed (colitis) mucosal tissue and microsomal fractions.
  • Assessed P-glycoprotein (P-gp) efflux and cytochrome P450 3A (CYP3A) mediated metabolism of tacrolimus and testosterone.

Main Results:

  • Slightly increased P-gp-related efflux was observed in colitis tissue.
  • Inflamed tissue showed higher mucosal metabolism of tacrolimus and testosterone.
  • Tacrolimus degradation correlated linearly with colitis severity (myeloperoxidase activity, R2 = 0.8299).
  • Immune-related cells were identified as a major contributor to altered mucosal drug metabolism.

Conclusions:

  • Inflammatory bowel disease (IBD) significantly alters drug metabolism within mucosal tissue.
  • Increased drug metabolism in inflamed tissue, driven by infiltrating immune cells, can reduce drug concentrations at the site of action.
  • These pathophysiological changes may necessitate adjustments in drug dosing for effective anti-inflammatory therapy in IBD.

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