Tacrolimus-Induced Neurotoxicity and Nephrotoxicity Is Ameliorated by Administration in the Dark Phase in Rats

1. Tacrolimus, a potent immunosuppressant, induces impaired renal function and neurological complications. We investigated the influence of dosing time on the neurotoxicity, nephrotoxicity, and immunosuppressive effect of tacrolimus in rats. 2. The repeated injection of tacrolimus in the light phase (8:00) produced a significantly greater increase than that in the dark phase (20:00) in the duration of harmine-induced tremors and in the blood urea nitrogen (BUN) concentration in rats. An immunosuppressive effect of tacrolimus on the xenotransplantation of mouse-to-rat skin grafts was apparent in the dark phase but not in the light phase. 3. The dosing time-dependent pharmacokinetic results were not observed when tacrolimus concentrations in rat whole blood were measured after a single or repeated injection in the light or dark phase. 4. These findings suggest that treatment in the active phase of the diurnal cycle ameliorates neurotoxicity and nephrotoxicity while maintaining the immunosuppressive effect of tacrolimus. The present findings have important implications for therapeutic approaches to avoid tacrolimus-induced neurotoxicity and nephrotoxicity.