Winnicki Wolfgang, Fichtenbaum Andreas, Mitulovič Goran, Herkner Harald, Regele Florina, Baier Michael, Zelzer Sieglinde, Wagner Ludwig, Sengoelge Guerkan
Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, 1090 Vienna, Austria.
Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
Biomedicines. 2022 Nov 10;10(11):2882. doi: 10.3390/biomedicines10112882.
Mycophenolic acid (MPA) is a widely used immunosuppressive agent and exerts its effect by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH), the main regulating enzyme of purine metabolism. However, significant unexplained differences in the efficacy and tolerability of MPA therapy pose a clinical challenge. Therefore, broad pharmacogenetic, pharmacokinetic, and pharmacodynamic approaches are needed to individualize MPA therapy. In this prospective cohort study including 277 renal transplant recipients, IMPDH2 rs11706052 SNP status was assessed by genetic sequencing, and plasma MPA trough levels were determined by HPLC and IMPDH enzyme activity in peripheral blood mononuclear cells (PBMCs) by liquid chromatography-mass spectrometry. Among the 277 patients, 84 were identified with episodes of biopsy-proven rejection (BPR). No association was found between rs11706052 SNP status and graft rejection (OR 1.808, and 95% CI, 0.939 to 3.479; = 0.076). Furthermore, there was no association between MPA plasma levels and BPR ( = 0.69). However, the patients with graft rejection had a significantly higher predose IMPDH activity in PBMCs compared to the controls without rejection at the time of biopsy (110.1 ± 50.2 vs. 95.2 ± 45.4 pmol/h; = 0.001), and relative to the baseline IMPDH activity before transplantation ( = 0.042). Our results suggest that individualization of MPA therapy, particularly through pharmacodynamic monitoring of IMPDH activity in PBMCs, has the potential to improve the clinical outcomes of transplant patients.
霉酚酸（MPA）是一种广泛使用的免疫抑制剂，通过抑制嘌呤代谢的主要调节酶肌苷5'-单磷酸脱氢酶（IMPDH）发挥作用。然而，MPA治疗在疗效和耐受性方面存在显著的无法解释的差异，这带来了临床挑战。因此，需要广泛的药物遗传学、药代动力学和药效学方法来实现MPA治疗的个体化。在这项纳入277名肾移植受者的前瞻性队列研究中，通过基因测序评估IMPDH2 rs11706052单核苷酸多态性（SNP）状态，通过高效液相色谱（HPLC）测定血浆MPA谷浓度，并通过液相色谱-质谱联用仪测定外周血单个核细胞（PBMC）中的IMPDH酶活性。在这277名患者中，84名被确诊为经活检证实的排斥反应（BPR）发作。未发现rs11706052 SNP状态与移植排斥之间存在关联（比值比1.808，95%置信区间为0.939至3.479；P = 0.076）。此外，MPA血浆水平与BPR之间也无关联（P = 0.69）。然而，与活检时无排斥反应的对照组相比，发生移植排斥的患者PBMC中的给药前IMPDH活性显著更高（110.1±50.2对95.2±45.4 pmol/h；P = 0.001），相对于移植前的基线IMPDH活性也更高（P = 0.042）。我们的结果表明，MPA治疗的个体化，特别是通过对PBMC中IMPDH活性进行药效学监测，有可能改善移植患者的临床结局。
