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Gastrointestinal toxicity of mycophenolate mofetil in rats: Effect of administration time

Ichrak Dridi1, Wafa Ben-Cherif1, Zohra Haouas2

  • 1a Laboratory of Pharmacology and.

Chronobiology International
|November 12, 2015
PubMed

Insights

Mycophenolate mofetil (MMF) intestinal toxicity in rats varies by dosing time. Administering MMF at 7 hours after light onset (HALO) caused severe gut toxicity, while 19 HALO showed better gastrointestinal tolerance.

Area of Science:

  • Pharmacology
  • Chronobiology
  • Gastroenterology

Background:

  • Mycophenolate mofetil (MMF) is an immunosuppressive agent with known gastrointestinal side effects.
  • The impact of drug administration timing on MMF toxicity is not well understood.
  • Circadian rhythms influence physiological processes, potentially affecting drug metabolism and toxicity.

Purpose of the Study:

  • To investigate the influence of circadian dosing time on the intestinal toxicity of mycophenolate mofetil (MMF) in rats.
  • To identify optimal dosing times for improved gastrointestinal tolerance of MMF.
  • To explore the relationship between MMF administration and circadian rhythms in the gut.

Main Methods:

  • Acute intraperitoneal administration of MMF (300 mg/kg) to rats at four different circadian stages (1, 7, 13, and 19 hours after light onset - HALO).
  • Assessment of intestinal toxicity, including histological changes (villous atrophy, inflammation) and biochemical markers (alkaline phosphatase activity, gut mucosa weight, protein content, disaccharidases).
  • Comparison of toxicity levels across different dosing times and with control groups.

Main Results:

  • MMF-induced intestinal toxicity significantly varied depending on the circadian dosing time in rats.
  • Severe toxicity in the duodenum and jejunum, characterized by villous atrophy, gland atrophy, and inflammation, was observed when MMF was administered at 7 HALO.
  • Administration at 7 HALO led to increased alkaline phosphatase activity and decreased gut mucosa weight, protein, and disaccharidases. Dosing at 19 HALO resulted in lower gut toxicity.

Conclusions:

  • A circadian rhythm in the intestinal toxicity of mycophenolate mofetil (MMF) exists in rats.
  • The middle of the dark-activity span (around 19 HALO) appears to be the optimal time for gastrointestinal tolerance (chronotolerance) of MMF.
  • These findings highlight the importance of considering circadian timing for optimizing MMF therapy and minimizing gut-related adverse effects.
Keywords:
Chronotoxicitycircadian rhythmintestinemycophenolate mofetilpresystemic enzymerat

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