Murine circadian time-dependent tolerance to the immunosuppressive agent mycophenolate mofetil (MMF)

Abstract

The present work aims to investigate whether the tolerance to mycophenolate mofetil (MMF) varies according to the circadian dosing time in rats. A total of 120 male Wistar rats were synchronized for three weeks to 12 h light/12 h dark. A potentially lethal dose of MMF (450 mg/kg, i.p.) was injected to different groups of animals at six different circadian stages (1, 5, 9, 13, 17, and 21 hours after light onset, HALO). Survival rate, body weight, and rectal temperature were used as three toxicity end-points. Drug dosing at 13 HALO resulted in 80% survival rate as compared to drug dosing at 17 HALO (20%). The Cosinor analysis revealed a significant ultradian rhythm (t = 8 h) in survival. The surviving treated rats exhibited a significant hyperthermia and body weight loss on days 3, 5, and 9. An ultradian component of τ = 8 h (p < 0.001) in the circadian body weight rhythm was detected by Cosinor (p < 0.0001).

Keywords:

• mycophenolate mofetil
• rats
• circadian rhythm
• survival
• rectal temperature

Acknowledgments

The authors would like to thank Mr Adel Rdissi for proof reading this article. This work was supported by “Le ministère de l'Enseignement Supérieur et de la Recherche Scientifique.”