BINDING OF TACROLIMUS (FK506) WITH HUMAN PLASMA-PROTEINS REEVALUATIONAND EFFECT OF MYCOPHENOLIC-ACID

Protein binding of tacrolimus (FK506) in human plasma was re-evaluated by equilibration dialysis and compared with that of FK506 previously reported by two different methods (about 99 and 77 % by an ultrafiltra tion and ultracentrifugation method, respectively). The binding determ ined in this study was about 99 % irrespective of FK506 concentrations added (0.5 - 10 ng/ml) and this value was very close to that estimate d by the ultrafiltration method. The effect of mycophenolic acid (MPA, an active form of the immunosuppressant mycophenolate mofetil) and it s glucuronide (MPAG, a major metabolite of mycophenolate mofetil in hu man plasma) on the binding was studied at concentration levels of 1 an d 10 ng/ml of FK506. The binding was not affected significantly by the addition of MPA (25 - 100 mu g/ml) and/or MPAG (100 - 1500 mu g/ml). FK506 has already been reported not to cause significant changes of pl asma protein binding of MPA. The results indicate that the unbound fra ction of FK506 is about 1 % in human plasma and that concomitant admin istration of FK506 and mycophenolic mofetil does not cause the drastic change of the binding of FK506 and MPA with human plasma proteins.