Administration time-dependent toxicity of a new immunosuppressive agent, tacrolimus (FK 506)

We have previously shown that blood concentrations of tacrolimus, a new immunosuppressive agent, were greater when it was administered orally at 10 pm than when it was administered at 10 am in rats. The present study was undertaken to examine whether the toxic effects of tacrolimus show administration time-dependent variations. Male Wistar rats were maintained under conditions of light from 7 am to 7 pm and dark from 7 pm to 7 am. Tacrolimus (1 and 4 mg/kg) was given orally at 10 am (day trial) or 10 pm (night trial) for 14 days. Blood samples were obtained at 24 hours after the final dosage of the agent. Weight gain was smaller in the night trial than in the day trial. Plasma concentrations of urea and creatinine increased significantly in the night trial while the elevations in these parameters were not observed in the day trial. These results suggest that the toxic effects of tacrolimus also vary with its time of oral dosage.