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Dosing-time dependent oxidative effects of an immunosuppressive drug "Mycophenolate Mofetil" on rat kidneys

Ichrak Dridi1, Wafa Ben-Cherif1, Hassiba Chahdoura2

  • 1Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Monastir, Tunisia.

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
|January 12, 2017
PubMed

Insights

Timing of mycophenolate mofetil (MMF) administration significantly impacts kidney toxicity and oxidative stress in rats. Dosing during the light-rest phase maximizes MMF renal toxicity, while dark-activity phase dosing minimizes it.

Area of Science:

  • Pharmacology
  • Chronobiology
  • Toxicology

Background:

  • Mycophenolate mofetil (MMF) is a crucial immunosuppressive agent.
  • Understanding the impact of circadian rhythms on drug toxicity is essential for optimizing therapeutic outcomes.
  • Previous research has not fully elucidated the influence of dosing time on MMF-induced renal toxicity.

Purpose of the Study:

  • To investigate the influence of circadian dosing times on kidney toxicity and oxidative stress induced by mycophenolate mofetil (MMF) in Wistar rats.
  • To identify specific dosing periods associated with increased or decreased MMF renal toxicity.

Main Methods:

  • Wistar rats received intraperitoneal injections of MMF (300mg/kg) at four different circadian time points (1, 7, 13, 19 hours after light onset).
  • Kidney tissues were analyzed after 3 days for oxidative stress markers (malondialdehyde, protein carbonyl, catalase, superoxide dismutase) and histological alterations.
  • Serum creatinine and urea levels were measured to assess renal function.

Main Results:

  • MMF administration at 7 hours after light onset (mid-light phase) significantly increased serum creatinine and urea, indicating renal toxicity.
  • This dosing time also elevated oxidative stress markers (malondialdehyde, protein carbonyl) and decreased antioxidant enzyme activity (catalase, superoxide dismutase), alongside observable kidney histopathology.
  • Conversely, MMF injection during the dark-activity phase resulted in minimal renal toxicity and oxidative stress.

Conclusions:

  • The timing of MMF administration critically influences its renal toxicity and associated oxidative stress in rats.
  • Maximum renal toxicity and oxidative damage occur when MMF is administered during the middle of the light-rest span.
  • Administering MMF during the dark-activity phase significantly mitigates its nephrotoxic effects, suggesting a chronotherapeutic approach for MMF treatment.
Keywords:
Circadian rhythmImmunosuppressive agentKidneyMMFOxidative stressRats

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