A novel leflunomide derivative, FK778, for immunosuppression after kidney transplantation in dogs.
BACKGROUND
Leflunomide and its metabolite, A77 1726, interfere with pyrimidine metabolism and exert potent immunosuppression in experimental organ transplantation. However, clinical use of the agents has been restrained because of an extended half-life. FK778, one synthetic malononitrilamide derived from A77 1726, is synthesized to overcome this problem while maintaining similar therapeutic efficacy.


METHODS
Immunosuppressive effect, pharmacokinetics, and adverse events of FK778, as a single drug treatment or combination with tacrolimus or cyclosporine, were determined in a canine kidney transplantation model. The agents were daily administered orally to the animals for 90 days after surgery. Animal survival, pharmacokinetics, biochemistry, hematology, and histopathology were evaluated.


RESULTS
FK778 at 4 mg/kg prolonged median survival of the control animals from 10 days to 30.5 days. Administration of 4 mg/kg FK778 with 0.3 mg/kg tacrolimus or 10 mg/kg cyclosporine increased median survival to 75.5 days and 50.5 days, respectively. In combined treatments, trough levels of FK778 at 4 mg/kg ranged between 40 microg/mL and 100 microg/mL after 1 month. Vomiting and diarrhea were common in animals given FK778. Bone marrow suppression was seen at higher doses.


CONCLUSIONS
FK778 is a promising new immunosuppressant that may be used in combination with current standard drugs in organ transplantation.
Jin
Maeng Bong
MB
Department of Organ Transplantation and Regenerative Medicine, and Laboratory of Molecular & Cellular Pathology, Hokkaido University School of Medicine, Sapporo, Japan.
Nakayama
Masato
M
Ogata
Toshiro
T
Fujita
Miri
M
Mino
Kazuhiro
K
Taniguchi
Masahiko
M
Suzuki
Tomomi
T
Shimamura
Tsuyoshi
T
Furukawa
Hiroyuki
H
Todo
Satoru
S
D000480:Alkynes; D000818:Animals; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D004285:Dogs; D005260:Female; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D007555:Isoxazoles / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D016030:Kidney Transplantation / Q000276:immunology; D009570:Nitriles; D016559:Tacrolimus / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity
D000480:Alkynes; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D016572:Cyclosporine; D016559:Tacrolimus