Vethe Nils Tore, Bremer Sara, Rootwelt Helge, Bergan Stein
Department of Medical Biochemistry, Rikshospitalet University Hospital, Oslo, Norway.
Ther Drug Monit. 2008 Dec;30(6):647-55. doi: 10.1097/FTD.0b013e31818955c3.
Mycophenolate mofetil is used in rejection prophylaxis after allograft transplantation. The highly variable pharmacokinetics and pharmacodynamics (PD) of the active moiety mycophenolic acid (MPA) render this drug attractive for therapeutic monitoring. The aim of this study was to characterize the exposure-response relationship for MPA to guide future strategies for individualized therapy based on PD monitoring. A single-dose (100, 250, 500, and 1000 mg mycophenolate mofetil) crossover exposure-response study of MPA PD in CD4 cells was performed in 5 healthy individuals. The activity of inosine 5'-monophosphate dehydrogenase (IMPDH) at time 0 ranged from 1.2 to 7.2 pmol per 10 cells/min. IMPDH was strongly inhibited by MPA; MPA EC50 (concentration required for 50% inhibition) of 2.3 mg/L was determined by a pooled data analysis. Decreased IMPDH gene expression was associated with the exposure to MPA. There were no immediate reductions of guanine nucleotides. On the contrary, a trend toward increased guanosine triphosphate was observed. IMPDH activity AUC0-12h approached maximum reduction at MPA AUC0-12h 22 mg x h/L (corresponding to the 500 mg dose), whereas plasma concentrations exceeding approximately 6 mg/L did not further increase the IMPDH inhibition. The results suggest that guanine nucleotides in circulating lymphocytes may not serve as immediate response biomarkers to MPA. Strategies for preventing over- or underexposure to MPA may be developed by means of IMPDH activity combined with MPA concentration measurement.
霉酚酸酯用于同种异体移植后的排斥反应预防。活性成分霉酚酸（MPA）高度可变的药代动力学和药效学（PD）使该药物成为治疗监测的理想选择。本研究的目的是表征MPA的暴露-反应关系，以指导基于PD监测的个体化治疗未来策略。在5名健康个体中进行了MPA PD的单剂量（100、250、500和1000 mg霉酚酸酯）交叉暴露-反应研究。0时刻肌苷5'-单磷酸脱氢酶（IMPDH）的活性范围为每10个细胞/分钟1.2至7.2 pmol。IMPDH受到MPA的强烈抑制；通过汇总数据分析确定MPA的EC50（50%抑制所需浓度）为2.3 mg/L。IMPDH基因表达的降低与MPA暴露有关。鸟嘌呤核苷酸没有立即减少。相反，观察到三磷酸鸟苷有增加的趋势。在MPA AUC0-12h为22 mg·h/L（对应于500 mg剂量）时，IMPDH活性AUC0-12h接近最大降低，而血浆浓度超过约6 mg/L并未进一步增加IMPDH抑制。结果表明，循环淋巴细胞中的鸟嘌呤核苷酸可能不是MPA的即时反应生物标志物。可以通过结合MPA浓度测量的IMPDH活性来制定预防MPA暴露过度或不足的策略。
