Immunosuppression with FK778 and mycophenolate mofetil in a rat cardiac transplantation model

FK778 blocks the dihydro-orotate dehydrogenase, necessary for pyrimidine synthesis, and mycophenolate mofetil (MMF) inhibits the inosine monophosphate dehydrogenase, a crucial enzyme for purine biosynthesis. Beneficial immunosuppressive effects have been suggested for the combination of both drugs. The Brown Norway-Lewis rat heterotopic heart transplantation model was used. FK778 (5 and 20 mg/kg/day), MMF (10 and 40 mg/kg/day), or a combination of both drugs for 10 days was used for prevention of acute graft rejection. Grafts of untreated animals were rejected after 6.2+/-0.4 days. Low-dose FK778 and low-dose MMF administration did not result in a significantly prolonged graft survival (6.7+/-0.8 and 8.7+/-1.4 days; P = not significant). Grafts of rats treated with high-dose FK778 or high-dose MMF survived significantly longer (17.0+/-2.8 and 20.7+/-3.8 days; P < 0.01). Concomitant use of low-dose FK778 with low-dose MMF produced synergistic interactions (mean survival time 12.3+/-2.9 days; P < 0.01; combination index = 0.85). High-dose drug combination (mean survival time 24.0+/-1.4 days) showed antagonistic drug interaction (combination index = 1.55) with increased toxic side effects.