研究麦考酚酸葡萄糖醛酸代谢物和霉酚酸酯在 Cedia MPA 测定中的交叉反应性。

Investigation of the crossreactivity of mycophenolic acid glucuronide metabolites and of mycophenolate mofetil in the Cedia MPA assay.

机构信息

Central Institute for Clinical Chemistry and Laboratory Medicine, Klinikum Stuttgart, Stuttgart, Germany.

出版信息

Ther Drug Monit. 2010 Feb;32(1):79-85. doi: 10.1097/FTD.0b013e3181cc342a.

PMID:20042920

Abstract

The immunosuppressant mycophenolic acid (MPA) used for solid organ transplantation is predominantly metabolized to a pharmacologically inactive phenolic glucuronide (MPAG) and, to a lesser extent, to the pharmacologically active acyl glucuronide (AcMPAG). The recently introduced CEDIA Mycophenolic Acid Assay from Microgenics has been reported to overestimate MPA in clinical samples and crossreactivity with AcMPAG has been suspected. A detailed investigation of the crossreactivity of AcMPAG and the prodrug mycophenolate mofetil (MMF) in the CEDIA assay is presented using pure substances. In addition, MPA concentrations in plasma were compared with a validated high-performance liquid chromatography-ultraviolet method. Plasma samples from kidney (KTx, n = 50), heart (HTx, n = 50), and liver (LTx, n = 50) transplant recipients were analyzed by the CEDIA (MPA) and a high-performance liquid chromatography-ultraviolet method (MMF, MPA, MPAG, AcMPAG). Crossreactivity of MMF (0.93-46.3 mg/L), MPAG (50-1000 mg/L), and AcMPAG (0.5-10 mg/L) was investigated using spiked drug-free plasma. Method comparison was performed using Bland & Altman and Passing & Bablok analysis. The method bias was correlated to AcMPAG concentrations using Spearman's rank correlation. Crossreactivity with AcMPAG and MMF was concentration-dependent and reached 215% and 143%, respectively. There was no crossreactivity with MPAG. The CEDIA assay showed a mean positive bias of 36.3% in patient samples. The mean bias was lowest with HTx samples (15%), 41.7% with KTx samples, and highest with LTx samples (52.3%). There was a positive correlation between the method bias and AcMPAG concentrations (r = 0.829; P < 0.001). No MMF was detected in patient samples. The CEDIA overestimates MPA concentrations on average by 36%. This bias is mainly the result of AcMPAG as previously observed with the EMIT MPA assay. It should be considered that the putative therapeutic range for MPA with the CEDIA assay will be higher than the range using high-performance liquid chromatography.

摘要

免疫抑制剂霉酚酸（MPA）主要用于实体器官移植，其代谢物为无药理活性的酚基葡萄糖醛酸（MPAG），其次为具有药理活性的酰基葡萄糖醛酸（AcMPAG）。最近，Microgenics 公司推出的 CEDIA 霉酚酸测定法被报道会高估临床样本中的 MPA，且 AcMPAG 的交叉反应性受到怀疑。本研究使用纯物质对 CEDIA 法中 AcMPAG 和前体药物霉酚酸酯（MMF）的交叉反应性进行了详细研究。此外，还将 MPA 浓度与经验证的高效液相色谱-紫外法进行了比较。采用 CEDIA（MPA）和高效液相色谱-紫外法（MMF、MPA、MPAG、AcMPAG）对 50 例肾移植（KTx）、50 例心脏移植（HTx）和 50 例肝移植（LTx）受者的血浆样本进行分析。采用添加无药血浆的方法研究 MMF（0.93-46.3mg/L）、MPAG（50-1000mg/L）和 AcMPAG（0.5-10mg/L）的交叉反应性。采用 Bland & Altman 和 Passing & Bablok 分析进行方法比较。方法偏差与 AcMPAG 浓度相关，采用 Spearman 秩相关进行分析。与 AcMPAG 和 MMF 的交叉反应性呈浓度依赖性，分别达到 215%和 143%。与 MPAG 无交叉反应性。CEDIA 法在患者样本中平均显示出 36.3%的正偏倚。HTx 样本的平均偏倚最低（15%），KTx 样本为 41.7%，LTx 样本最高（52.3%）。方法偏差与 AcMPAG 浓度呈正相关（r=0.829；P<0.001）。患者样本中未检测到 MMF。CEDIA 法平均高估 MPA 浓度 36%。这种偏差主要是 AcMPAG 的结果，正如之前 EMIT MPA 法所观察到的。应注意，与高效液相色谱法相比，CEDIA 法测定 MPA 的治疗范围可能更高。