title: Gastrointestinal toxicity of mycophenolate mofetil in rats: Effect of administration time.
abstract: This study investigates whether the intestinal toxicity of the immunosuppressive agent "mycophenolate mofetil (MMF)" varied according to the circadian dosing-time in rats. MMF (300 mg/kg) was acutely administered by i.p. route in rats at four different circadian stages (1, 7, 13 and 19 hours after light onset, HALO). The results obtained showed that MMF-induced intestinal toxicity depends on circadian dosing-time in rats. A severe toxicity in the duodenum and jejunum was observed when the drug was administered at 7 HALO compared to controls and to other circadian times. This toxicity appeared in the form of villous and Liberkhun gland atrophy and nodular inflammation. At this dosing-time, MMF induced a significant increase of phosphatase alkaline activity and a significant decrease of gut mucosa weight, protein content and disaccharidases activities. Conversely, MMF dosing at 19 HALO induced lower gut toxicity, irrespective of type of toxicity explored. These data suggest the existence of a circadian rhythm of gut toxicity for this immunosuppressive agent and the best time of gastrointestinal tolerance (chronotolerance) of this agent was observed in the middle of the dark-activity span of rats.
authors.affiliation: a Laboratory of Pharmacology and.
authors.forename: Ichrak
authors.initials: I
authors.lastname: Dridi
authors.affiliation: a Laboratory of Pharmacology and.
authors.forename: Wafa
authors.initials: W
authors.lastname: Ben-Cherif
authors.affiliation: b Laboratory of Histology Embryology and Cytogenetic , Faculty of Medicine, University of Monastir , Monastir , Tunisia .
authors.forename: Zohra
authors.initials: Z
authors.lastname: Haouas
authors.affiliation: a Laboratory of Pharmacology and.
authors.forename: Karim
authors.initials: K
authors.lastname: Aouam
authors.affiliation: c Laboratory of Biomonitoring of the Environment , Faculty of Science of Bizerte, Carthage University , Tunis , Tunisia , and.
authors.forename: Mossadok
authors.initials: M
authors.lastname: Ben-Attia
authors.affiliation: d Unit of Chronobiology, Foundation A. de Rothschild Paris , Paris , France.
authors.forename: Alain
authors.initials: A
authors.lastname: Reinberg
authors.affiliation: a Laboratory of Pharmacology and.
authors.forename: Naceur A
authors.initials: NA
authors.lastname: Boughattas
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D002940:Circadian Rhythm / Q000187:drug effects*; D004361:Drug Tolerance / Q000502:physiology; D004386:Duodenum / Q000601:surgery; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007583:Jejunum / Q000601:surgery; D008297:Male; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid
keywords: Chronotoxicity; circadian rhythm; intestine; mycophenolate mofetil; presystemic enzyme; rat