Potential value of high-dose mizoribine as rescue therapy for ongoing acute humoral rejection

Abstract

Summary Mizoribine (MZ) inhibits the proliferation of lymphocytes selectively via inhibition of inosine monophosphate dehydrogenase, like mycophenolate mofetil (MMF). The clinical dosage of MZ (2–5 mg/kg) is much lower than that of MMF (20–60 mg/kg). The purpose of this study was to examine whether high‐dose MZ would be effective for treatment of acute humoral rejection. Renal transplantation was performed in a different pig strain combination. Group 1 (n = 2) received no treatment. Group 2 (n = 4) received cyclosporine microemulsion (6 mg/kg) and prednisolone (0.1 mg/kg) as baseline immunosuppression. Groups 3 (n = 4), 4 (n = 4) and 5 (n = 4) were additionally treated with MZ for rescue therapy, 30, 10 and 3 mg/kg, respectively, immediately after rejection was observed. All pigs developed acute vascular rejection between days 4 and 8. Complete reversal of acute rejection including reduction of elevated serum creatinine, suppression of anti‐donor antibody production and pathological finding, was obtained in 3/4 (group 3), 1/4 (group 4) and 0/4 (group 5). Rescue with high‐dose MZ (30 mg/kg) reversed ongoing acute humoral rejection. Such a high dose of MZ was tolerable for pigs. However, leukocytopenia was observed when MZ trough level was maintained over 10 μg/ml. Treatment with high‐dose MZ would be applicable to a clinical trial, if blood level is carefully monitored.

Combination Effect of Mycophenolate Mofetil with Mizoribine on Cell Proliferation Assays and in a Mouse Heart Transplantation Model

“…This is supported by our and others (36,37) data in vivo and in vitro which were showed the MZ had lower potential to inhibit cell proliferation assays and rejection in mouse heart transplantation than MMF. In addition, it has been reported that high-dose MZ therapy was effective experimentally for ongoing acute humoral rejection (38) and clinically for frequently relapsing steroid-dependent nephritic syndrome (39). Following these results, a clinical trial of highdose of MZ therapy for renal transplantation is being conducted in several Japanese hospitals.…”

Effect of Salt Intake on Bioavailability of Mizoribine in Healthy Japanese Males

“…2) Mizoribine is a highly hydrophilic and weakly acidic compound, 3) and is not metabolized in the body. Mizoribine binds poorly to plasma proteins (2.3%), 4) and is excreted predominantly in the urine (81.8% at 6 h after oral administration of 100 mg mizoribine in healthy subjects) 5) ; therefore, renal function has been considered to be one of the main causes of the pharmacokinetic variability of mizoribine. On the other hand, Ihara et al evaluated the pharmacokinetics of mizoribine in 14 kidney transplant recipients.…”

Involvement of Multiple Transporters-mediated Transports in Mizoribine and Methotrexate Pharmacokinetics

“…There is a positive relationship between the serum level of mizoribine and its clinical efficacy without causing severe adverse effects [22,23,24]. This indicates that pulse therapy or high-dose of mizoribine is applicable in clinical use.…”