Thi Minh Thuan Nguyen, Mourad Michel, Capron Arnaud, Tshinanu Flora Musuamba, Vincent Marie-Françoise, Wallemacq Pierre
Clinical Chemistry Department, Cliniques Universitaires St Luc, Brussels, Belgium; Louvain Center for Toxicology and Applied Pharmacology, Université catholique de Louvain, UCL, Brussels, Belgium.
Department of Surgery, Surgery and Abdominal Transplantation Division, Cliniques Universitaires St Luc, Brussels, Belgium.
Clin Biochem. 2015 Apr;48(6):401-5. doi: 10.1016/j.clinbiochem.2014.12.005. Epub 2014 Dec 16.
Little is known about the correlation between the inosine-monophosphate dehydrogenase (IMPDH) activity and mycophenolic acid (MPA) concentrations in peripheral-blood-mononuclear cells (PBMCs), where the drug is acting. The aim of this study was to analyze the relationship between plasma or PBMC MPA levels, as pharmacokinetic (PK) markers, and the intracellular IMPDH enzyme activity, as a pharmacodynamic (PD) biomarker, in kidney transplantation.
Forty de novo renal transplant patients were enrolled in this prospective study. The sampling was performed on the day before transplantation and at T0, T1.5 and T3.5 following the morning dose, on days 2, 4 and 10 post-transplantation. All subjects were treated with a fixed MMF dose (500 mg twice-a-day). IMPDH activities were determined by HPLC, and MPA plasma or PBMC concentrations were obtained by LC-MSMS.
Important inter-patient variability was observed both for the PK and PD biomakers. Pre-dose IMPDH activity, surprisingly, increased during the 10 days post-transplantation. As expected, a significant inverse relationship was found between IMPDH activities and MPA concentrations in both plasma and PBMCs. A significant correlation was found between plasma and PBMC MPA values. Maximum IMPDH inhibition was found mostly at T1.5, before returning to its pre-dose levels at T3.5. IMPDH inhibition at T1.5 better correlated with plasma MPA AUC(0-3.5) (p=0.027) than with PBMC AUC(0-3.5) (p=0.323). Mean MPA plasma concentrations paralleled the enzyme inhibition profiles and decreased strongly at T3.5, whereas the decreasing slope of MPA concentrations in PBMCs appeared slower.
These findings suggest that PBMC MPA concentrations do not provide any better correlation with the IMPDH activity than plasma MPA values, most likely due to the correlation between plasma and PBMC MPA levels and to the important interpatient variability both in MPA levels and enzyme activities.
对于肌苷单磷酸脱氢酶（IMPDH）活性与药物作用部位外周血单个核细胞（PBMC）中霉酚酸（MPA）浓度之间的相关性，人们了解甚少。本研究旨在分析肾移植中作为药代动力学（PK）标志物的血浆或PBMC中MPA水平与作为药效学（PD）生物标志物的细胞内IMPDH酶活性之间的关系。
40例初发肾移植患者纳入本前瞻性研究。在移植前一天以及移植后第2、4和10天早晨给药后的T0、T1.5和T3.5进行采样。所有受试者均接受固定剂量的霉酚酸酯（MMF）治疗（500mg，每日两次）。通过高效液相色谱法（HPLC）测定IMPDH活性，通过液相色谱-串联质谱法（LC-MSMS）获得MPA血浆或PBMC浓度。
在PK和PD生物标志物方面均观察到患者间存在显著差异。令人惊讶的是，给药前IMPDH活性在移植后10天内有所增加。正如预期的那样，在血浆和PBMC中，IMPDH活性与MPA浓度之间均发现显著的负相关关系。血浆和PBMC中MPA值之间存在显著相关性。最大IMPDH抑制作用大多出现在T1.5，之后在T3.5恢复到给药前水平。T1.5时的IMPDH抑制作用与血浆MPA的AUC(0 - 3.5)（p = 0.027）的相关性优于与PBMC的AUC(0 - 3.5)（p = 0.323）的相关性。MPA血浆平均浓度与酶抑制曲线平行，并在T3.5时大幅下降，而PBMC中MPA浓度的下降斜率似乎较慢。
这些发现表明，PBMC中MPA浓度与IMPDH活性的相关性并不比血浆MPA值更好，这很可能是由于血浆和PBMC中MPA水平之间的相关性以及MPA水平和酶活性方面患者间存在显著差异。
