Administration of FK506 for 15 days at daily doses of 3.2 mg/kg p.o., 10 mg/kg p.o., 0.32 mg/kg i.m., or 1 mg/kg i.m. to heart-allografted rats resulted in a significant prolongation of graft survival time. The best graft acceptance was obtained in the 1 mg/kg i.m. group: all six grafts survived longer than 50 days, and two of them, indefinitely. The31P nuclear magnetic resonance (NMR) technique was utilized to investigate in vivo the energy metabolism of grafts. The ratios of inorganic phosphate (Pi)/phosphocreatine (PCr) and PCr/ATP were useful parameters for monitoring cardiac insufficiency after transplantation. The mean ratios of Pi/PCr and PCr/ATP in syngeneic grafts were 0.38±0.11 and 1.88±0.42, respectively. In the control allografts, a rapid increase in the Pi/PCr ratio and a decrease in the PCr/ATP ratio were found from day 5. During the period of FK 506 administration, increased Pi/PCr and decreased PCr/ATP ratios were also observed in all groups. The changes in these ratios were related with FK506 dosage. The results suggest that FK506 has a side-effect on graft metabolism. The metabolism tended to improve upon cessation of the drug in all grafts, but it worsened again in 3-3 1/2 weeks in the rats treated with 3.2 mg/kg p.o., 10 mg/kg p.o., or 0.32 mg/kg i.m. This seemed to be due to graft rejection. In the 1 mg/kg i.m. group, lowering of the Pi/PCr ratio and elevation of the PCr/ATP ratio were observed after the withdrawal of FK506, and these ratios remained stable until the end of the observation period. In conclusion, FK506 was found to be a potent immunosuppressant with a significant side-effect on graft metabolism.
All Science Journal Classification (ASJC) codes
- Cardiology and Cardiovascular Medicine