Circadian variation of mycophenolate mofetil pharmacokinetics in rats

The present work aims to investigate whether the pharmacokinetics of the active metabolite mycophenolic acid (MPA) varies according to the circadian dosing-time of mycophenolate mofetil (MMF). A total of 180 male Wistar rats aged 8 weeks and synchronized for 3 weeks to 12 h light and 12 h dark were used. A single dose of 200 mg/kg of MMF was administrated in rats by i.p route at either of the four different circadian stages (1, 7, 13, and 19 Hours After Light Onset, HALO) (45 rats/circadian time). At each circadian stage, blood samples were collected at 5, 10, 15, 20, 30 min, 1 h, 1 h 30 min, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h and 24 h following drug injection. Plasma MPA concentrations were analyzed for each sample using a validated high-performance liquid chromatography (RP-HPLC) method. Tmax of MPA remained similar whatever the circadian time of injection mean Tmax=30 min). However, the peak of plasma concentration Cmax varied significantly according to the circadian dosing-time. Maximum and minimum Cmax were obtained when MMF was injected at 7 HALO (69.1 μg/ml) and at 19 HALO (22.7 ± 1.74 μg/ml) respectively. AUC0-24 varied significantly according to the circadian-time of injection (166.33 ± 10.54 mg h/L at 7 HALO vs 80.27 ± 2.33 mg h/L at 19 HALO) (p<0.05). The highest and lowest mean values of plasma clearance (CL calculated as Dos/AUC) were observed at 19 HALO (2.45 ± 0.07 L/h/kg) and at 7 HALO (1.08 ± 0.06 L/h/kg) respectively (p<0.05). Cosinor showed a circadian rhythm in the pharmacokinetic parameters Cmax, AUC0-24 and plasma clearance. The mechanism of circadian rhythm in MMF tolerance might be partly explained by the circadian variation of pharmacokinetics since the time (7 HALO) of maximum hematological and digestive toxicity corresponds to that of the lowest plasma clearance on the highest Cmax and AUC0-24 of MMF.