The interaction between FK778 and tacrolimus in the prevention of rat cardiac allograft rejection is dose dependent.
OBJECTIVE
The synthetic malononitrilamide FK778 inhibits T- and B-cell responsiveness, phagocyte effector function, exerts inhibitory activity against cytomegalovirus, and is thus one of the most promising new immunosuppressive drugs. The aim of this study was to evaluate the combination of FK778 and tacrolimus in a high-responder rat cardiac transplantation model.


METHODS
The Brown Norway-Lewis rat strain combination was used to investigate graft survival after 10 days of posttransplant oral therapy with FK778 (5 or 20 mg/kg), tacrolimus (2 or 8 mg/kg), or combination regimens at varying doses (5+2 mg/kg, 10+1 mg/kg, or 20+8 mg/kg). Grafts were harvested after cessation of cardiac contractions. Combination indices (CI) were calculated for drug combinations.


RESULTS
In untreated recipients, allograft survival was 6.2+/-0.4 days. FK778 at 20 mg/kg and tacrolimus at 2 or 8 mg/kg significantly prolonged graft survival to a mean survival time (MST) of 17.0+/-2.8, 18.5+/-2.7, and 25.0+/-2.5 days, respectively. The two low-dose drug combinations achieved a graft survival of 23.2+/-2.9 and 25.2+/-3.1 days, which was significantly longer compared with FK778 at 5 mg/kg, FK778 at 20 mg/kg, and tacrolimus at 2 mg/kg (P </=0.003) and was similar to that of high-dose tacrolimus therapy (8 mg/kg). The drugs showed synergistic interactions (CI values of 0.62 and 0.52, respectively). With the high-dose drug combination, MST was 30.0+/-4.1 days, which was significantly longer compared with all other groups (P </=0.012). However, drugs showed only additive interaction (CI=0.95), and recipients suffered enhanced toxic side effects.


CONCLUSIONS
This study provides evidence that FK778 and tacrolimus show supportive interaction in their immunosuppressive potency that is synergistic in low-dose combinations and additive in higher doses.
Deuse
Tobias
T
Department of Cardiovascular Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Schrepfer
Sonja
S
Reichenspurner
Hermann
H
D000480:Alkynes; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007555:Isoxazoles / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D009570:Nitriles; D051381:Rats; D011914:Rats, Inbred BN; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects
D000480:Alkynes; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D016559:Tacrolimus