Chronopharmacology of Mizoribine in Collagen-Induced Arthritis Rats

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  • Kanasaki Yuko
    Department of Hospital Pharmacy, Nagasaki University Hospital of Medicine and Dentistry, Japan Department of Hospital Pharmacy, Nagasaki University Hospital of Medicine and Dentistry, Japan
  • Tomonari Mari
    Department of Hospital Pharmacy, Nagasaki University Hospital of Medicine and Dentistry, Japan Department of Medical Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Japan Department of Hospital Pharmacy, Nagasaki University Hospital of Medicine and Dentistry, Japan Department of Medical Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Japan
  • Sasaki Hitoshi
    Department of Hospital Pharmacy, Nagasaki University Hospital of Medicine and Dentistry, Japan Department of Hospital Pharmacy, Nagasaki University Hospital of Medicine and Dentistry, Japan
  • To Hideto
    Department of Hospital Pharmacy, Nagasaki University Hospital of Medicine and Dentistry, Japan Department of Medical Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Japan Department of Hospital Pharmacy, Nagasaki University Hospital of Medicine and Dentistry, Japan Department of Medical Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Japan

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We previously reported that higher therapeutic effects were obtained in rheumatoid arthritis (RA) patients and RA model animals when the dosing-times of methotrexate and tacrolimus were chosen according to the 24-h rhythms of the inflammatory response. Mizoribine (MZR) is an immunosuppressive agent and is used against RA in the same manner as methotrexate and tacrolimus. In this study, we examined whether a dosing-time dependency of the therapeutic effect of MZR could be detected in collagen-induced arthritis (CIA) rats. To measure C-reactive protein (CRP) and tumor necrosis factor (TNF)-α levels, blood was collected from CIA rats at different times. MZR was administered at two different dosing-times based on these findings and its effects and toxicity were examined. CRP and TNF-α concentrations in blood showed significant 24-h rhythms. The exacerbation of arthritis and excessive increase in leukocytes in CIA rats were markedly lower in the group treated with MZR at the dark phase than those of the group treated with MZR at the light phase. These findings suggest that the therapeutic index of RA therapy may be improved by administering MZR at a time in the day when the inflammatory reaction begins to activate.

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