Huang Yun-Fen, Huang Ya-Ching, Ning Hsiao-Chen, Lin Chia-Ni
Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan.
J Food Drug Anal. 2022 Jun 15;30(2):283-292. doi: 10.38212/2224-6614.3404.
Mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), specific inhibitors of lymphocyte proliferation, are commonly used as adjuvant therapy with calcineurin inhibitor agents after kidney transplantation. After administration, MMF and EC-MPS are hydrolyzed to mycophenolic acid (MPA), the active form of the drug, which must be monitored due to its narrow therapeutic window, drug-drug interactions, and large intra-and inter-individual pharmacokinetic variability despite a fixed dose. Monitoring plasma MPA level is recommended to maintain the drug within the therapeutic window, optimize its efficacy, and minimize side effects. This study aims to develop a method for quantifying MPA and its major metabolites (mycophenolic acid glucuronide [MPAG]) using on-line solid phase extraction (SPE) coupled with an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) in kidney transplant patients. The linearity of MPA and MPAG were 0.3-13.6 μg/mL and 2.6-232.9 μg/mL, respectively (r > 0.999). The relative error of accuracy was <15%. The within-run and between-run imprecision was <5.8%. No carryover, ion suppression, or ion enhancement were observed. This method was used to analysis of 351 plasma samples from renal transplant patients after MMF or EC-MPS using this method showed large pharmacokinetic variability between patients. Analysis of the same samples by immunoassay showed a large positive bias compared with our validated UPLC-MS/MS method, averaging 15.1%. These results suggest that this UPLC-MS/MS method is more effective than immunoassay for quantitation of MPA and its metabolites in clinical samples.
霉酚酸酯（MMF）和肠溶包衣的霉酚酸钠（EC-MPS）是淋巴细胞增殖的特异性抑制剂，常用于肾移植后与钙调神经磷酸酶抑制剂联合进行辅助治疗。给药后，MMF和EC-MPS会水解为药物的活性形式霉酚酸（MPA），由于其治疗窗窄、存在药物相互作用以及尽管剂量固定但个体内和个体间药代动力学变异性大，因此必须对其进行监测。建议监测血浆MPA水平，以将药物维持在治疗窗内、优化其疗效并使副作用最小化。本研究旨在开发一种方法，用于在肾移植患者中使用在线固相萃取（SPE）结合超高效液相色谱-串联质谱（UPLC-MS/MS）对MPA及其主要代谢物（霉酚酸葡糖苷酸[MPAG]）进行定量分析。MPA和MPAG的线性范围分别为0.3-13.6μg/mL和2.6-232.9μg/mL（r>0.999）。准确度的相对误差<15%。批内和批间精密度<5.8%。未观察到残留、离子抑制或离子增强现象。使用该方法对351例接受MMF或EC-MPS治疗的肾移植患者的血浆样本进行分析，结果显示患者之间药代动力学变异性很大。与我们验证的UPLC-MS/MS方法相比，通过免疫测定法对相同样本进行分析显示存在较大的正偏差，平均为15.1%。这些结果表明，对于临床样本中MPA及其代谢物的定量分析，这种UPLC-MS/MS方法比免疫测定法更有效。
