title: A transient increase of calcineurin phosphatase activity in living-donor kidney transplant recipients with acute rejection.
abstract: We describe the longitudinal follow-up of calcineurin activity and its clinical relevance in 4 de novo living-donor kidney transplant recipients treated with cyclosporine (n=1) or tacrolimus (n=3). The calcineurin activity in peripheral blood mononuclear cells was measured in combination with therapeutic drug monitoring during hospitalization. Serial blood samplings were performed after the oral administration of each drug to evaluate the temporal pharmacokinetic and pharmacodynamic profiles. Significant changes in enzyme activity were evaluated in relation to clinical outcomes. A nadir of calcineurin activity occurred at the maximum blood drug concentration within 4 h post-dose in most cases. Unlike cyclosporine, tacrolimus partially suppressed calcineurin activity throughout the dosing interval compared to the pre-dose level (cyclosporine, 62-67% inhibition; tacrolimus, 13-35% inhibition). Notably, calcineurin activity rapidly increased a few days before the onset of acute rejection in 2 patients, 1 receiving cyclosporine and 1 receiving tacrolimus, despite the achievement of therapeutic trough blood concentrations. These preliminary findings indicate that therapeutic monitoring of calcineurin activity in addition to the measurement of blood drug concentrations may be helpful to evaluate the pharmacodynamic effects of cyclosporine and tacrolimus early after renal transplantation.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Fukudo
authors.forename: Ikuko
authors.initials: I
authors.lastname: Yano
authors.forename: Toshiya
authors.initials: T
authors.lastname: Katsura
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ito
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kamoto
authors.forename: Osamu
authors.initials: O
authors.lastname: Ogawa
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Inui
mesh_terms: D000017:ABO Blood-Group System / Q000276:immunology; D000328:Adult; D001769:Blood / Q000187:drug effects / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016903:Drug Monitoring; D006084:Graft Rejection / Q000097:blood* / Q000188:drug therapy / Q000201:enzymology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D007676:Kidney Failure, Chronic / Q000628:therapy; D016030:Kidney Transplantation / Q000276:immunology* / Q000379:methods; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D010744:Phosphoric Monoester Hydrolases / Q000097:blood*; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000017:ABO Blood-Group System; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003404:Creatinine; C120817:calcineurin phosphatase; D010744:Phosphoric Monoester Hydrolases; D016559:Tacrolimus