Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai 200040, China.
Department of Nephropathy, Huashan Hospital, Fudan University, Shanghai 200040, China.
Clin Chim Acta. 2018 Oct;485:333-339. doi: 10.1016/j.cca.2018.06.042. Epub 2018 Jun 28.
The immunosuppressive agent mycophenolic acid (MPA) is a non-competitive, reversible inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH). Thus, IMPDH activity can serve as a potential pharmacodynamic biomarker to optimize dosing of MPA.
Peripheral blood mononuclear cells were isolated from 2 mL blood samples and an in vitro enzymatic reaction was subsequently performed for 120 min. To determine IMPDH activity in Chinese healthy volunteers and renal transplant patients, a high performance liquid chromatography assay was established and validated by subtracting adenosine monophosphate (AMP) from blank samples for eliminating exogenous AMP interference.
The accuracy of our method ranged between -0.8% and 12.5%, and the precision ranged between 0.7% and 6.3%. The mean value of IMPDH activity across 11 healthy volunteers was 46.60 ± 14.28 μmol/s/mol AMP. A negative relationship between MPA concentration and IMPDH activity was observed in four renal transplant patients treated with MPA 13 days post-transplantation, while the inhibitory rate of IMPDH activity ranged from 24% to 42%.
A bioanalytical assay for IMPDH quantification was optimized and evaluated. The differences in the pharmacodynamics of MPA between Asians and Caucasians may provide some evidence for dosing differences among ethnicities.
免疫抑制剂霉酚酸（MPA）是肌苷-5'-单磷酸脱氢酶（IMPDH）的非竞争性、可逆抑制剂。因此，IMPDH 活性可作为优化 MPA 剂量的潜在药效学生物标志物。
从 2mL 血样中分离外周血单核细胞，随后进行 120min 的体外酶反应。为了测定中国健康志愿者和肾移植患者的 IMPDH 活性，建立了一种高效液相色谱法，并通过从空白样品中减去单磷酸腺苷 (AMP) 来消除外源性 AMP 干扰进行验证。
我们方法的准确度在-0.8%至 12.5%之间，精密度在 0.7%至 6.3%之间。11 名健康志愿者的 IMPDH 活性平均值为 46.60±14.28μmol/s/mol AMP。在 4 名接受 MPA 治疗的肾移植患者中，移植后 13 天观察到 MPA 浓度与 IMPDH 活性之间存在负相关，而 IMPDH 活性的抑制率在 24%至 42%之间。
优化并评估了用于 IMPDH 定量的生物分析测定法。亚洲人和高加索人之间 MPA 药效学的差异可能为不同种族之间的剂量差异提供一些证据。
