Establishment of an animal model with side effects induced by mycophenolate mofetil and pharmacohistological analysis of them.
Mycophenolate mofetil (MMF) is used for immunosuppression after organ transplantation, but gastrointestinal side effects including diarrhea are sometimes observed with this drug. We sought to construct on animal model of diarrhea with MMF in rodents.


METHODS
BALB/Cj mice, weighing 25 g received 500 mg /kg of MMF, 60 mg/kg of levofloxacin (LVFX), 1000 mg/kg of Hangeshashin-to (HST), which is traditional Kampo medicine. This cocktail was administered orally to MMF, LVFX, HST, MMF+LVFX, and MMF+LVFX+HST groups for 21 days. We measured the water content fecal collected on days 1, 4, 8, 11, 14, 18, and 21. Feces on day 21 were cultured for identification of fecal flora. Mice were sacrificed on day 21, with blood samples collected to measure mycophenolic acid (MPA) concentrations by HPLC. Jejunum, cecum, and colon were taken for histological evaluation.


RESULTS
Significant weight loss of mice and increased fecal water content of were observed in MMF and MMF+LVFX but not in MMF+LVFX+HST groups. Serum MPA levels didn't differ in MMF-administered groups. Inflammatory changes in intestinal villi were observed in the cecum in MMF and MMF+LVFX groups. A change in fecal flora was observed in LVFX-administered groups.


CONCLUSIONS
Diarrhea induced by MMF in a rodent model produced inflammatory changes in the cecum. LVFX seemed to change the activity of beta-glucuronidase in the fecal flora. HST suppressed fecal softening induced by MMF in this animal model.
Watanabe
M
M
Department of Surgery, Graduate School of Comphrehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan. motowide@aol.com
Yuzawa
K
K
Homma
M
M
Ohkohchi
N
N
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003967:Diarrhea / Q000139:chemically induced*; D002149:Energy Intake; D005247:Feeding Behavior / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000009:adverse effects; D064704:Levofloxacin; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives*; D015242:Ofloxacin / Q000494:pharmacology; D015431:Weight Loss / Q000187:drug effects*
D007166:Immunosuppressive Agents; D064704:Levofloxacin; D015242:Ofloxacin; D009173:Mycophenolic Acid