Langman L J, LeGatt D F, Yatscoff R W
Department of Laboratory Medicine and Pathology, University of Alberta Hospitals, Edmonton, Canada.
Clin Chem. 1995 Feb;41(2):295-9.
Pharmacodynamic monitoring of the biological effect of immunosuppressive drugs provides an alternative to traditional therapeutic drug monitoring. We chose this method to investigate mycophenolic acid (MPA), an immunosuppressive drug that mediates its effect by inhibition of IMP dehydrogenase (IMPDH), a key enzyme in the de novo biosynthesis of purines. Using an assay developed for measuring IMPDH activity in whole blood, we found the concentration of MPA required for 50% inhibition of enzyme activity to be in the range of 2.0-5.0 mg/L for both human and rabbit blood. The amount of enzyme activity in whole blood depended on the concentration of the leukocytes, was unaffected by the type of anticoagulant used, and was stable in blood specimens stored for as long as 48 h at 4 degrees C. An inverse relationship was found between plasma MPA concentrations and IMPDH activity in rabbits administered a single dose of RS-61443, the prodrug of MPA. Maximal inhibition of IMPDH activity (by approximately 60%) occurs at peak concentrations of MPA; as the concentration of the drug decreases postdose, the enzyme activity gradually increases with little or no inhibition being observed 24 h postdose.
免疫抑制药物生物学效应的药效学监测为传统治疗药物监测提供了一种替代方法。我们选择这种方法来研究霉酚酸（MPA），这是一种免疫抑制药物，它通过抑制肌苷单磷酸脱氢酶（IMPDH）发挥作用，IMPDH是嘌呤从头生物合成中的关键酶。使用一种开发用于测量全血中IMPDH活性的检测方法，我们发现对于人和兔血，抑制酶活性50%所需的MPA浓度在2.0 - 5.0 mg/L范围内。全血中的酶活性量取决于白细胞浓度，不受所用抗凝剂类型的影响，并且在4℃下储存长达48小时的血液标本中保持稳定。在单剂量给予MPA的前体药物RS - 61443的兔中，发现血浆MPA浓度与IMPDH活性之间呈负相关。IMPDH活性的最大抑制（约60%）发生在MPA的峰值浓度时；随着给药后药物浓度降低，酶活性逐渐增加，给药后24小时几乎没有抑制作用。
