Department of Hospital Pharmacy, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015CE, Rotterdam, The Netherlands.
J Pharmacokinet Pharmacodyn. 2009 Dec;36(6):541-64. doi: 10.1007/s10928-009-9136-6. Epub 2009 Nov 11.
Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is used to prevent graft rejection in renal transplant recipients. MPA is glucuronidated to the metabolite MPAG, which exhibits enterohepatic recirculation (EHC). MPA binds for 97% and MPAG binds for 82% to plasma proteins. Low plasma albumin concentrations, impaired renal function and coadministration of cyclosporine have been reported to be associated with increased clearance of MPA. The aim of the study was to develop a population pharmacokinetic model describing the relationship between MMF dose and total MPA (tMPA), unbound MPA (fMPA), total MPAG (tMPAG) and unbound MPAG (fMPAG). In this model the correlation between pharmacokinetic parameters and renal function, plasma albumin concentrations and cotreatment with cyclosporine was quantified. tMPA, fMPA, tMPAG and fMPAG concentration-time profiles of renal transplant recipients cotreated with cyclosporine (n = 48) and tacrolimus (n = 45) were analyzed using NONMEM. A 2- and 1-compartment model were used to describe the pharmacokinetics of fMPA and fMPAG. The central compartments of fMPA and fMPAG were connected with an albumin compartment allowing competitive binding (bMPA and bMPAG). tMPA and tMPAG were modeled as the sum of the bound and unbound concentrations. EHC was modeled by transport of fMPAG to a separate gallbladder compartment. This transport was decreased in case of cyclosporine cotreatment (P < 0.001). In the model, clearance of fMPAG decreased when creatinine clearance (CrCL) was reduced (P < 0.001), and albumin concentration was correlated with the maximum number of binding sites available for MPA and MPAG (P < 0.001). In patients with impaired renal function cotreated with cyclosporine the model adequately described that increasing fMPAG concentrations decreased tMPA AUC due to displacement of MPA from its binding sites. The accumulated MPAG could also be reconverted to MPA by the EHC, which caused increased tMPA AUC in patients cotreated with tacrolimus. Changes in CrCL had hardly any effect on fMPA exposure. A decrease in plasma albumin concentration from 0.6 to 0.4 mmol/l resulted in ca. 38% reduction of tMPA AUC, whereas no reduction in fMPA AUC was seen. In conclusion, a pharmacokinetic model has been developed which describes the relationship between dose and both total and free MPA exposure. The model adequately describes the influence of renal function, plasma albumin and cyclosporine co-medication on MPA exposure. Changes in protein binding due to altered renal function or plasma albumin concentrations influence tMPA exposure, whereas fMPA exposure is hardly affected.
霉酚酸（MPA）是霉酚酸酯（MMF）的活性化合物，用于预防肾移植受者的移植物排斥。MPA 被葡糖醛酸化生成代谢物 MPAG，后者表现出肠肝循环（EHC）。MPA 结合率为 97%，MPAG 结合率为 82%至血浆蛋白。据报道，低血浆白蛋白浓度、肾功能损害和环孢素合用与 MPA 清除率增加有关。研究的目的是建立一个描述霉酚酸酯剂量与总 MPA（tMPA）、游离 MPA（fMPA）、总 MPAG（tMPAG）和游离 MPAG（fMPAG）之间关系的群体药代动力学模型。在该模型中，定量描述了药代动力学参数与肾功能、血浆白蛋白浓度和环孢素合用之间的相关性。采用 NONMEM 分析了接受环孢素（n=48）和他克莫司（n=45）联合治疗的肾移植受者的 tMPA、fMPA、tMPAG 和 fMPAG 浓度-时间曲线。使用 2 室和 1 室模型描述 fMPA 和 fMPAG 的药代动力学。fMPA 和 fMPAG 的中央隔室通过允许竞争性结合（bMPA 和 bMPAG）的白蛋白隔室连接。tMPA 和 tMPAG 被建模为结合和未结合浓度的总和。EHC 通过将 fMPAG 转运到单独的胆囊隔室来建模。在环孢素合用的情况下，这种转运减少（P <0.001）。在该模型中，当肌酐清除率（CrCL）降低时，fMPAG 的清除率降低（P <0.001），并且白蛋白浓度与 MPA 和 MPAG 的最大结合位点数量相关（P <0.001）。在接受环孢素治疗的肾功能受损的患者中，该模型充分描述了增加的 fMPAG 浓度由于 MPA 从其结合位点被置换而降低 tMPA AUC。累积的 MPAG 也可以通过 EHC 重新转化为 MPA，这导致接受他克莫司治疗的患者 tMPA AUC 增加。CrCL 的变化对 fMPA 暴露几乎没有影响。血浆白蛋白浓度从 0.6 降至 0.4 mmol/L 导致 tMPA AUC 降低约 38%，而 fMPA AUC 无降低。总之，已经开发了一种药代动力学模型，该模型描述了剂量与总 MPA 和游离 MPA 暴露之间的关系。该模型充分描述了肾功能、血浆白蛋白和环孢素合用对 MPA 暴露的影响。由于肾功能或血浆白蛋白浓度的变化导致的蛋白结合变化会影响 tMPA 暴露，而 fMPA 暴露则几乎不受影响。
