Bremer Sara, Vethe Nils T, Rootwelt Helge, Jørgensen Pål F, Stenstrøm Jean, Holdaas Hallvard, Midtvedt Karsten, Bergan Stein
Department of Medical Biochemistry, Rikshospitalet University Hospital, Oslo, Norway.
J Transl Med. 2009 Jul 27;7:64. doi: 10.1186/1479-5876-7-64.
Mycophenolic acid (MPA) is widely used as part of immunosuppressive regimens following allograft transplantation. The large pharmacokinetic (PK) and pharmacodynamic (PD) variability and narrow therapeutic range of MPA provide a potential for therapeutic drug monitoring. The objective of this pilot study was to investigate the MPA PK and PD relation in combination with belatacept (2nd generation CTLA4-Ig) or cyclosporine (CsA).
Seven renal allograft recipients were randomized to either belatacept (n = 4) or cyclosporine (n = 3) based immunosuppression. Samples for MPA PK and PD evaluations were collected predose and at 1, 2 and 13 weeks posttransplant. Plasma concentrations of MPA were determined by HPLC-UV. Activity of inosine monophosphate dehydrogenase (IMPDH) and the expressions of two IMPDH isoforms were measured in CD4+ cells by HPLC-UV and real-time reverse-transcription PCR, respectively. Subsets of T cells were characterized by flow cytometry.
The MPA exposure tended to be higher among belatacept patients than in CsA patients at week 1 (P = 0.057). Further, MPA concentrations (AUC0-9 h and C0) increased with time in both groups and were higher at week 13 than at week 2 (P = 0.031, n = 6). In contrast to the postdose reductions of IMPDH activity observed early posttransplant, IMPDH activity within both treatment groups was elevated throughout the dosing interval at week 13. Transient postdose increments were also observed for IMPDH1 expression, starting at week 1. Higher MPA exposure was associated with larger elevations of IMPDH1 (r = 0.81, P = 0.023, n = 7 for MPA and IMPDH1 AUC0-9 h at week 1). The maximum IMPDH1 expression was 52 (13-177)% higher at week 13 compared to week 1 (P = 0.031, n = 6). One patient showed lower MPA exposure with time and did neither display elevations of IMPDH activity nor IMPDH1 expression. No difference was observed in T cell subsets between treatment groups.
The significant influence of MPA on IMPDH1 expression, possibly mediated through reduced guanine nucleotide levels, could explain the elevations of IMPDH activity within dosing intervals at week 13. The present regulation of IMPDH in CD4+ cells should be considered when interpreting measurements of IMPDH inhibition.
霉酚酸（MPA）作为同种异体移植术后免疫抑制方案的一部分被广泛应用。MPA较大的药代动力学（PK）和药效学（PD）变异性以及狭窄的治疗窗为治疗药物监测提供了可能性。本试点研究的目的是研究MPA与贝拉西普（第二代CTLA4-Ig）或环孢素（CsA）联合应用时的PK和PD关系。
7例肾移植受者被随机分为接受基于贝拉西普（n = 4）或环孢素（n = 3）的免疫抑制治疗。在给药前以及移植后1、2和13周采集用于MPA PK和PD评估的样本。MPA的血浆浓度通过高效液相色谱-紫外检测法（HPLC-UV）测定。分别通过HPLC-UV和实时逆转录聚合酶链反应在CD4+细胞中测量肌苷单磷酸脱氢酶（IMPDH）的活性以及两种IMPDH亚型的表达。通过流式细胞术对T细胞亚群进行表征。
在第1周时，贝拉西普组患者的MPA暴露量倾向于高于环孢素组患者（P = 0.057）。此外，两组患者的MPA浓度（AUC0-9 h和C0）均随时间增加，且在第13周时高于第2周（P = 0.031，n = 6）。与移植后早期观察到的给药后IMPDH活性降低相反，在第13周时，两个治疗组在整个给药间隔内IMPDH活性均升高。从第1周开始，还观察到IMPDH1表达在给药后有短暂增加。较高的MPA暴露与IMPDH1更大程度的升高相关（r = 0.81，P = 0.023，第1周时MPA和IMPDH1的AUC0-9 h，n = 7）。与第1周相比，第13周时IMPDH1的最大表达量高出52（13 - 177）%（P = 0.031，n = 6）。1例患者的MPA暴露量随时间降低，且既未表现出IMPDH活性升高，也未表现出IMPDH1表达升高。治疗组之间在T细胞亚群方面未观察到差异。
MPA对IMPDH1表达的显著影响可能是通过鸟嘌呤核苷酸水平降低介导的，这可以解释在第13周给药间隔内IMPDH活性的升高。在解释IMPDH抑制的测量结果时，应考虑目前CD4+细胞中IMPDH的调节情况。
