Department of Biochemistry, University of Pavia, Pharmacokinetics Unit, Pavia, Italy.
Br J Clin Pharmacol. 2010 Jan;69(1):38-50. doi: 10.1111/j.1365-2125.2009.03542.x.
Long-term mycophenolate mofetil (MMF) therapy may induce inosine 5'-monophosphate dehydrogenase (IMPDH) activity in peripheral blood mononuclear cells (PBMCs), thus decreasing MMF immunosuppressive properties. Pharmacodynamic monitoring was used to investigate whether biological activity is altered after long-term therapy.
IMPDH activity was measured in PBMC samples from 54 stable kidney transplant patients, already on MMF (for at least 3 months), before (t(0)) and 2 h after (t(2)) MMF morning dose administration; levels were monitored for up to 15 months, together with total mycophenolic acid (MPA) and free MPA concentrations.
During the 15 months' monitoring, t(0) IMPDH activity in transplant recipients increased from 5.9 +/- 3.7 nmol h(-1) mg(-1)[95% confidence interval (CI) 4.9, 6.9] to 9.0 +/- 3.9 nmol h(-1) mg(-1) (95% CI 7.2, 10.8), with an intra- and interpatient variability of 28% and 42%. Five patients experienced acute rejection during the follow-up: t(0) IMPDH activity was increased during rejection vs. nonrejection, and the trend was significantly higher in rejecting than in nonrejecting subjects for the whole monitoring period.
Even though a correlation has been found between IMPDH activity and rejection, its efficacy as a predictive tool in long-term transplant outcomes may be affected by high interpatient variability; on the other hand, continuous monitoring of the IMPDH trend could make an effective prognostic parameter of rejection. Other trials also including pre-transplant data on both IMPDH expression and activity are warranted to better assess their role as biomarkers for MPA effect in clinical practice.
已知信息：
霉酚酸（MPA）是一种有效的、选择性的、可逆的肌苷 5'-单磷酸脱氢酶（IMPDH）抑制剂，是从头合成鸟苷三磷酸的限速酶。
个体间 IMPDH 活性的巨大差异可能是 MPA 治疗效果和副作用差异的原因。
在免疫抑制治疗期间，全血中观察到 IMPDH 活性的诱导。
新增信息：
我们的数据是在长期接受吗替麦考酚酯（MMF）治疗的肾移植受者中获得的，他们接受了不同组合的免疫抑制剂（环孢素、他克莫司、西罗莫司）治疗，并具有不同的治疗持续时间（移植后长达 8.8 年）。
在我们 12 个月的观察期间，我们观察到的 IMPDH 活性呈上升趋势，在排斥反应患者中明显高于非排斥反应患者。
目的：
方法：
结果：
在 15 个月的监测期间，移植受者的 t(0)IMPDH 活性从 5.9 +/- 3.7 nmol h(-1) mg(-1)[95%置信区间（CI）4.9, 6.9]增加到 9.0 +/- 3.9 nmol h(-1) mg(-1)（95% CI 7.2, 10.8），个体内和个体间的变异性分别为 28%和 42%。
在随访期间，有 5 名患者发生急性排斥反应：排斥反应期间 t(0)IMPDH 活性增加，排斥反应患者的趋势明显高于非排斥反应患者，整个监测期间均如此。
结论：
尽管已经发现 IMPDH 活性与排斥反应之间存在相关性，但它作为长期移植结果的预测工具的效果可能受到个体间差异的影响；另一方面，连续监测 IMPDH 趋势可能成为排斥反应的有效预后参数。
还需要其他包括移植前 IMPDH 表达和活性的临床试验，以更好地评估它们在临床实践中作为 MPA 效果的生物标志物的作用。
