Department of Medicine and Transplantation, Ospedali Riuniti di Bergamo-Mario Negri Institute for Pharmacological Research, Via G B Camozzi 3, Bergamo, Italy.
Transplantation. 2011 Sep 15;92(5):550-6. doi: 10.1097/TP.0b013e318225dbd0.
In kidney transplantation, the pharmacokinetics of mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is influenced by concomitant immunosuppressive therapy, including cyclosporine (CsA). However, whether in the setting of immunosuppressive therapy minimization CsA still affects MPA pharmacokinetics, particularly in relation to varying degree of renal graft function deterioration, remains ill defined.
One hundred thirty-five complete MPA profiles were sequentially collected from 56 kidney transplant recipients given MMF and low-dose CsA as part of their immunosuppressive therapy. MPA pharmacokinetic parameters were correlated with blood CsA area under the curve (AUC0-12) and graft function as measured glomerular filtration rate (GFR). The relative contribution of CsA exposure and GFR to MPA kinetics in relation to other clinical parameters was determined by multivariate analysis.
Dose-adjusted MPA AUC0-12 negatively correlated with CsA AUC0-12. MPA exposure significantly increased when CsA AUC0-12 was below 2000 ng hr/mL. Stratification of MPA profiles according to stages of renal dysfunction showed that dose-adjusted MPA AUC0-12 was higher (P<0.001) in patients with severe (stage 4: 70.37±27.93 μg hr/mL/g MMF) than in those with mild (stage 2: 47.46±11.66 μg hr/mL/g MMF) or moderate (stage 3; 47.48±15.22 μg hr/mL/g MMF) renal insufficiency. At multivariate analysis GFR, serum albumin and hemoglobin levels, use of gastroprotective medications, and time posttransplant were identified as independent determinants of MPA AUC0-12.
In stable renal transplant recipients given MMF, tapering CsA dose and deterioration of renal graft function contribute to increased MPA exposure. Thus, monitoring plasma MPA pharmacokinetics should be advised, especially in patients on minimized CsA therapy with severe renal insufficiency.
在肾移植中，霉酚酸（MPA）的药代动力学，霉酚酸酯（MMF）的活性化合物，受伴随的免疫抑制治疗的影响，包括环孢素（CsA）。然而，在免疫抑制治疗最小化的情况下，CsA 是否仍然会影响 MPA 的药代动力学，特别是与不同程度的肾移植物功能恶化有关，仍然没有明确的定义。
对 56 例接受 MMF 和低剂量 CsA 作为免疫抑制治疗一部分的肾移植受者进行了 135 次完整的 MPA 谱序采集。MPA 药代动力学参数与血 CsA 曲线下面积（AUC0-12）和肾小球滤过率（GFR）相关。通过多变量分析确定 CsA 暴露和 GFR 与其他临床参数对 MPA 动力学的相对贡献。
剂量调整后的 MPA AUC0-12 与 CsA AUC0-12 呈负相关。当 CsA AUC0-12 低于 2000nghr/ml 时，MPA 暴露显著增加。根据肾功能障碍的阶段对 MPA 谱进行分层显示，在严重肾功能不全（第 4 期：70.37±27.93μghr/ml/g MMF）患者中，剂量调整后的 MPA AUC0-12 高于轻度（第 2 期：47.46±11.66μghr/ml/g MMF）或中度（第 3 期：47.48±15.22μghr/ml/g MMF）肾功能不全患者（P<0.001）。多变量分析确定 GFR、血清白蛋白和血红蛋白水平、使用胃保护药物以及移植后时间是 MPA AUC0-12 的独立决定因素。
在接受 MMF 治疗的稳定肾移植受者中，CsA 剂量的减少和移植物肾功能的恶化导致 MPA 暴露增加。因此，建议监测血浆 MPA 药代动力学，特别是在接受最小化 CsA 治疗和严重肾功能不全的患者中。
