El Haggan W, Ficheux M, Debruyne D, Rognant N, Lobbedez T, Allard C, Coquerel A, Ryckelynck J P, Hurault de Ligny B
Department of Nephrology and Renal Transplantation, Caen University Hospital, Caen, France.
Transplant Proc. 2005 Mar;37(2):864-6. doi: 10.1016/j.transproceed.2004.12.217.
Mycophenolic acid (MPA) pharmacokinetics exhibit large variability in transplant recipients and may be altered due to concurrent immunosuppressants. Little is known about the influence of sirolimus (SRL) on MPA pharmacokinetics in kidney transplant patients.
We studied the areas under concentration-time curves (AUC) for MPA in 15 patients receiving immunosuppression combining SRL with mycophenolate mofetil (MMF). The pharmacokinetic measurements were performed in all patients using three MMF dosing regimens (0.5 g twice a day, 0.75 g twice a day, 1 g twice a day). Similar blood AUC profiles were also sampled from 12 patients treated with a fixed dose of MMF 1 g twice a day and cyclosporine (CsA). MPA was measured using HPLC; the AUC0-12 of MPA was determined by the trapezoidal method using four sampling time points: C0, C1, C3, C5.
While patients on SRL were receiving 0.75 g MMF twice a day, mean AUC0-12 and C0 values of MPA were comparable to those of patients receiving CsA and 1 g MMF twice a day (54.1 +/- 17.6 and 3 +/- 1.87 vs 51.7 +/- 16.7 mg.h/L and 2.76 +/- 1.57 mg/L, respectively). On the other hand, 0.5 g MMF twice a day with SRL therapy resulted in AUC0-12 and C0 values of MPA of 32.3 +/- 12.6 mg.h/L and 2.32 +/- 1.72 mg/L, respectively, whereas, 1 g MMF twice a day with SRL resulted in AUC0-12 and C0 values of MPA of 70.9 +/- 19.3 mg.h/L and 4.7 +/- 2.44 mg/L, respectively.
These findings demonstrate that MPA exposure in the presence of SRL is higher than that with CsA. It appears that the MMF dose should be reduced to 0.75 g twice a day in patients receiving SRL to obtain AUC0-12 of MPA levels comparable to that in patients treated with CsA and MMF 1 g twice a day.
霉酚酸（MPA）的药代动力学在移植受者中表现出很大的变异性，并且可能会因同时使用免疫抑制剂而改变。关于西罗莫司（SRL）对肾移植患者MPA药代动力学的影响知之甚少。
我们研究了15例接受SRL与霉酚酸酯（MMF）联合免疫抑制治疗的患者中MPA的浓度-时间曲线下面积（AUC）。使用三种MMF给药方案（每日两次，每次0.5 g；每日两次，每次0.75 g；每日两次，每次1 g）对所有患者进行药代动力学测量。还从12例接受固定剂量每日两次、每次1 g MMF和环孢素（CsA）治疗的患者中采集了相似的血液AUC曲线。使用高效液相色谱法测量MPA；MPA的AUC0-12通过梯形法使用四个采样时间点（C0、C1、C3、C5）确定。
当接受SRL治疗的患者每日两次服用0.75 g MMF时，MPA的平均AUC0-12和C0值与接受CsA和每日两次服用1 g MMF的患者相当（分别为54.1±17.6和3±1.87，以及51.7±16.7 mg·h/L和2.76±1.57 mg/L）。另一方面，SRL治疗联合每日两次服用0.5 g MMF导致MPA的AUC0-12和C0值分别为32.3±12.6 mg·h/L和2.32±1.72 mg/L，而SRL联合每日两次服用1 g MMF导致MPA的AUC0-12和C0值分别为70.9±19.3 mg·h/L和4.7±2.44 mg/L。
这些发现表明，在SRL存在的情况下MPA的暴露量高于CsA。对于接受SRL治疗的患者，似乎应将MMF剂量减至每日两次，每次0.75 g，以使MPA水平的AUC0-12与接受CsA和每日两次服用1 g MMF治疗的患者相当。
