Langman L J, LeGatt D F, Halloran P F, Yatscoff R W
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.
Transplantation. 1996 Sep 15;62(5):666-72. doi: 10.1097/00007890-199609150-00022.
The combination of pharmacokinetic and pharmacodynamic monitoring of immunosuppressive drugs provides a novel method for the optimization of drug dosing. We chose to investigate this with the use of mycophenolic acid (MPA), an immunosuppressive drug that mediates its effect by the inhibition of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo biosynthesis of purines. The relationship between MPA concentration in plasma, IMPDH activity in whole blood, and nucleotide concentration in lymphocytes was investigated in renal-transplant recipients, who were randomized to receive either mycophenolate mofetil (MMF) (n = 5) or azathioprine (AZA) (n = 7), in combination with cyclosporine and prednisone. Blood samples were collected throughout the dosing interval. Pharmacokinetic analysis revealed substantial variability among the patients in the absorption and clearance of MPA. An inverse relationship was found between the MPA concentration of IMPDH activity in whole blood. The peak concentration of MPA achieved at 1 hr after dosing resulted in approximately 40% inhibition of IMPDH activity. As the MPA concentration decreased throughout the dosing interval, there was a gradual restoration of IMPDH activity. The inhibition of IMPDH activity (P < 0.05) in MMF-treated patients as compared with the AZA-treated controls was maintained for approximately 8 hr after dosing. No statistically significant (P > 0.05) difference between the predose and the 12 hr postdose activity was observed. The concentrations of guanine nucleotides, GDP and GMP, were significantly lower than in the AZA-treated group at most of the time points after dosing; however, considerable variability was observed. The measurement of the pharmacodynamic response to immunosuppressive drugs may provide not only a mechanism to predict the most appropriate dosing regimen, but also a viable alternative to traditional therapeutic drug monitoring, by assessing the overall state of immunosuppression.
免疫抑制药物的药代动力学和药效学监测相结合，为优化药物剂量提供了一种新方法。我们选择使用霉酚酸（MPA）来研究这一方法，MPA是一种免疫抑制药物，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。在肾移植受者中研究了血浆中MPA浓度、全血中IMPDH活性和淋巴细胞中核苷酸浓度之间的关系，这些受者被随机分为接受霉酚酸酯（MMF）（n = 5）或硫唑嘌呤（AZA）（n = 7），并联合环孢素和泼尼松治疗。在整个给药间隔期采集血样。药代动力学分析显示患者间MPA的吸收和清除存在很大差异。发现全血中MPA浓度与IMPDH活性呈负相关。给药后1小时达到的MPA峰值浓度导致IMPDH活性约40%的抑制。随着给药间隔期内MPA浓度降低，IMPDH活性逐渐恢复。与AZA治疗的对照组相比，MMF治疗的患者给药后约8小时内IMPDH活性的抑制（P < 0.05）得以维持。给药前和给药后12小时的活性之间未观察到统计学显著差异（P > 0.05）。给药后大多数时间点，鸟嘌呤核苷酸GDP和GMP的浓度显著低于AZA治疗组；然而，观察到相当大差异。对免疫抑制药物的药效学反应进行测量，不仅可以提供一种预测最合适给药方案的机制，还可以通过评估免疫抑制的整体状态，为传统治疗药物监测提供一种可行的替代方法。
