title: Prophylactic treatment of antibody-mediated rejection with high-dose mizoribine and pharmacokinetic study.
abstract: Although mizoribine (MZ), which inhibits inosine monophosphate dehydrogenase in the same way as mycophenolate mofetil, recently proved more effective when higher doses were administered than previously approved, neither the optimal dosage nor blood concentration has yet been clarified. We aimed at investigating the effect of high-doses of MZ on prevention of anti-donor antibody (Ab) production and acute Ab-mediated rejection (AMR) on the basis of the pharmacokinetic profile in a pig kidney transplantation model. Group 1 (n = 5) received cyclosporin microemulsion (6 mg/kg) and prednisolone (0.1 mg/kg). Groups 2, 3 and 4 (each n = 5) were treated, respectively, with 30, 10 and 3 mg/kg of MZ in addition to cyclosporin and prednisolone. The incidences of AMR in groups 1, 2, 3 and 4 were 5/5, 1/5, 3/5 and 5/5, respectively. Anti-donor IgG/IgM Ab levels (relative to pretransplantation levels) on day 14 in groups 1, 2, 3 and 4 were 10.3/9.3, 1.8/1.0, 2.3/1.8 and 6.5/3.5, respectively. While only 2 (28.6%) of seven pigs with Cmax > 3 microg/ml during the first 2 weeks had AMR, 7 (87.5%) of eight pigs with Cmax < 3 microg/ml elicited anti-donor Abs and experienced AMR (P = 0.0406). Effective Cmax seemed to be over 3 microg/ml at minimum. Higher doses of MZ efficiently prevented AMR. However, therapeutic drug monitoring is essential before clinical application.
authors.affiliation: Department of Surgery II, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: DaGe
authors.initials: D
authors.lastname: Liu
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Takaharu
authors.initials: T
authors.lastname: Nagasaka
authors.forename: Yuko
authors.initials: Y
authors.lastname: Miwa
authors.forename: Yong
authors.initials: Y
authors.lastname: Ma
authors.forename: Itsuo
authors.initials: I
authors.lastname: Yokoyama
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kuzuya
authors.forename: Tadashi
authors.initials: T
authors.lastname: Oikawa
authors.forename: Kunio
authors.initials: K
authors.lastname: Morozumi
authors.forename: Kazuharu
authors.initials: K
authors.lastname: Uchida
authors.forename: Akimasa
authors.initials: A
authors.lastname: Nakao
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016030:Kidney Transplantation; D011239:Prednisolone / Q000627:therapeutic use; D012263:Ribonucleosides / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D013552:Swine; D013556:Swine, Miniature
chemical_list: D007166:Immunosuppressive Agents; D012263:Ribonucleosides; C010052:mizoribine; D016572:Cyclosporine; D011239:Prednisolone