Circadian variation in haematological toxicity of the immunosuppressive agent “Mycophenolate Mofetil” in rats

Because of biological rhythms, drug efficiency and toxicity vary according to the time of administration of the drug. This study investigates whether the haematological toxicity of the immunosuppressive agent Mycophenolate Mofetil varies according to the circadian dosing-time in rats. 300 mg/kg of Mycophenolate Mofetil was injected by i.p. route to different groups of animals at six different circadian stages (1, 7, 13, and 19 hours after light onset, i.e., HALO). Mycophenolate Mofetil treatment induced a significant decrease at 7 HALO in red blood cells (–18%), in haemoglobin rate (–15%) and in white blood cells (–54%). These parameters followed a circadian rhythm with an acrophase located at the end of the light-rest phase. A significant thrombocytopenia was observed according to Mycophenolate Mofetil the circadian dosing-time. In the controls, the number of platelets followed a circadian rhythm. Mycophenolate Mofetil modified this rhythm which became an 8-h ultradian rhythm. The data indicate that, the Mycophenolate Mofetil-induced haematological toxicity was maximum when the drug was administered in the middle of the light-rest phase, which is physiologically analogous to the end of the activity of the diurnal phase in human patients.