title: Dosing time-dependency of the arthritis-inhibiting effect of tacrolimus in mice.
abstract: Stiffness and cytokine in blood levels show 24-h rhythms in rheumatoid arthritis (RA) patients. We previously revealed that higher therapeutic effects were obtained in RA patients and RA model animals when the dosing time of methotrexate was chosen according to the 24-h rhythms to cytokine. In this study, we examined whether a dosing time-dependency of the therapeutic effect of tacrolimus (TAC) could be detected in collagen-induced arthritis (CIA) and MRL/lpr mice. To measure the levels of cytokines and serum amyloid A (SAA), blood was collected from CIA mice at different times. TAC was administered at two different dosing times based on these findings and its effects on arthritis and toxicity were examined. Plasma tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), and SAA concentrations showed obvious 24-h rhythms with higher levels during the light phase and lower levels during the dark phase after RA crisis. The arthritis score and leukocyte counts were significantly lower in the group treated at 2 h after the light was turned on (HALO) than in the control and 14 HALO-treated groups. Our findings suggest that choosing an optimal dosing time could lead to the effective treatment of RA by TAC.
authors.affiliation: Clinical Pharmacokinetics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Obayashi
authors.forename: Mari
authors.initials: M
authors.lastname: Tomonari
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Yoshimatsu
authors.forename: Ryuji
authors.initials: R
authors.lastname: Fukuyama
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ieiri
authors.forename: Shun
authors.initials: S
authors.lastname: Higuchi
authors.forename: Hideto
authors.initials: H
authors.lastname: To
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D024043:Collagen Type II / Q000633:toxicity; D055870:Drug Chronotherapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D015850:Interleukin-6 / Q000097:blood; D007958:Leukocyte Count; D007964:Leukocytosis / Q000517:prevention & control; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008813:Mice, Inbred ICR; D019463:Mice, Inbred MRL lpr; D051437:Renal Insufficiency / Q000139:chemically induced; D000685:Serum Amyloid A Protein / Q000032:analysis; D012720:Severity of Illness Index; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D018501:Antirheumatic Agents; D024043:Collagen Type II; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D000685:Serum Amyloid A Protein; D014409:Tumor Necrosis Factor-alpha; D016559:Tacrolimus