Langman L J, Nakakura H, Thliveris J A, LeGatt D F, Yatscoff R W
Departments of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.
Ther Drug Monit. 1997 Apr;19(2):146-52. doi: 10.1097/00007691-199704000-00005.
Pharmacodynamic (PD) monitoring of immunosuppressive drugs provides a novel approach to optimization of drug therapy in transplant recipients. We chose to investigate this using 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. A comparison of the relationship between PD versus drug level monitoring was performed using a heterotopic cardiac transplant in New Zealand white rabbits. The animals were divided into four different treatment groups. Control animals were administered the drug vehicle, the treatment groups were administered mycophenolate mofetil (MMF) at doses of 40, 80, and 160 mg/kg/day. Statistically significant (p < 0.05) prolongation of graft survival was obtained at the 160 mg/kg/day dose group. The mean MPA concentration at this dose was approximately 2.5 mg/l, suggesting that this concentration may provide adequate immunosuppression. An increase in IMPDH activity appeared a few days prior to rejection, suggesting that measurement of enzyme activity may have potential for use as a marker of graft rejection. A significant (p < 0.05) relationship exists between MPA concentration and graft survival and the former with dose of MMF. There was a negative correlation (p = 0.17) between MPA concentration and IMPDH activity, while a trend (p = 0.37) to inverse relationship between graft survival and IMPDH activity was found. The data suggests that the measurement of the biological response may provide a useful adjunct to traditional therapeutic drug monitoring (TDM) for optimization of dosing of immunosuppressive drugs.
免疫抑制药物的药效学（PD）监测为优化移植受者的药物治疗提供了一种新方法。我们选择使用霉酚酸（MPA）进行研究，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。利用新西兰白兔的异位心脏移植，对PD与药物浓度监测之间的关系进行了比较。将动物分为四个不同的治疗组。对照组给予药物赋形剂，治疗组分别给予剂量为40、80和160mg/kg/天的霉酚酸酯（MMF）。在160mg/kg/天剂量组获得了具有统计学意义（p<0.05）的移植物存活期延长。该剂量下的平均MPA浓度约为2.5mg/l，表明该浓度可能提供足够的免疫抑制作用。在排斥反应前几天，IMPDH活性出现增加，提示酶活性的测量可能有潜力用作移植物排斥反应的标志物。MPA浓度与移植物存活之间存在显著（p<0.05）关系，且与MMF剂量也存在显著关系。MPA浓度与IMPDH活性之间存在负相关（p = 0.17），而移植物存活与IMPDH活性之间发现呈负相关趋势（p = 0.37）。数据表明，生物反应的测量可能为优化免疫抑制药物给药的传统治疗药物监测（TDM）提供有用的辅助手段。
