Brunet M, Martorell J, Oppenheimer F, Vilardell J, Millán O, Carrillo M, Rojo I, Corbella J
Toxicology Department, Hospital Clinic, Barcelona, Spain.
Transpl Int. 2000;13 Suppl 1:S301-5. doi: 10.1007/s001470050348.
Suboptimal doses of mycophenolate mofetil (MMF) are frequently employed in renal transplant (Tx) patients, with drug-related side effects or low weight. The aim of this study was to compare the mycophenolic acid (MPA) pharmacokinetic profile and its pharmacodynamic effect on patients receiving either standard (2 g) or low (1.5 g or 1 g) MMF doses, in order to evaluate the therapeutic efficacy of such low doses in inhibiting IMPDH activity. Twenty-seven stable renal Tx recipients aged 18-65 years, with a post-Tx follow-up of 38.5 +/- 44.8 months (6-166 months), receiving 1 g (n = 10), 0.75 g (n = 7) and 0.5 g (n = 10) MMF twice a day in association with cyclosporine and prednisone, were included. The control group was made up of untreated healthy volunteers (n = 5). Plasma concentrations of MPA were analyzed by reverse-phase HPLC. IMPDH activity was determined in lymphocytes by the measurement of 3H release from [2,8-(3)H] hypoxantine. The mean value of areas under the concentration-time curves (AUC(0-12)) of MPA throughout the 12-h dosing interval in patients treated with 2 g was higher than the corresponding data in patients receiving 1.5 g or 1 g bid, but no statistical differences were observed between the three groups. There was no correlation between MPA-AUC(0-12) values and MMF dose (expressed in g/day or g/kg per day). Predose MPA concentrations correlated only weakly with the respective MPA-AUC(0-12) values (r2 from 0.385 to 0.655), whereas an acceptable correlation was observed between MPA Cmax and MPA-AUC(0-12) (r2 from 0.626 to 0.759) in 2 g, 1.5 g, and 1 g MMF groups. An inverse relationship between MPA concentrations and IMPDH activity was observed. In general, the maximum MPA concentration was achieved from 1 h to 2 h after dosing, and the maximum inhibition of IMPDH was also from 1 h to 2 h after dosing. The evaluation of IMPDH activity demonstrated that there was a significant statistical difference between samples from 0 to 1 h (P = 0.008) and 0 to 2 h (P = 0.04). In conclusion, concentration-time profiles of renal transplant recipients administered 0.75 g and 0.5 g twice a day are slightly lower than those from the 2 g group, but nor significantly. On the other hand, inhibition of IMPDH activity was comparable in the three groups, indicating considerable interindividual pharmacodynamic variability. Pharmacodynamic monitoring of the degree of immunosuppression and its correlation with MPA plasma concentrations will be assessed further in future studies.
霉酚酸酯（MMF）的次优剂量常用于肾移植（Tx）患者，这些患者存在药物相关副作用或体重较低。本研究的目的是比较接受标准剂量（2 g）或低剂量（1.5 g或1 g）MMF的患者的霉酚酸（MPA）药代动力学特征及其药效学效应，以评估此类低剂量在抑制肌苷单磷酸脱氢酶（IMPDH）活性方面的治疗效果。纳入了27例年龄在18 - 65岁的稳定肾移植受者，肾移植术后随访时间为38.5±44.8个月（6 - 166个月），他们每天两次联合环孢素和泼尼松接受1 g（n = 10）、0.75 g（n = 7）和0.5 g（n = 10）的MMF治疗。对照组由未经治疗的健康志愿者组成（n = 5）。采用反相高效液相色谱法分析MPA的血浆浓度。通过测量[2,8 - (3)H]次黄嘌呤释放的3H来测定淋巴细胞中的IMPDH活性。接受2 g MMF治疗的患者在12小时给药间隔内MPA的浓度 - 时间曲线下面积（AUC(0 - 12)）的平均值高于接受1.5 g或1 g bid治疗的患者的相应数据，但三组之间未观察到统计学差异。MPA - AUC(0 - 12)值与MMF剂量（以g/天或g/kg/天表示）之间无相关性。给药前MPA浓度与各自的MPA - AUC(0 - 12)值仅呈弱相关（r2为0.385至0.655），而在2 g、1.5 g和1 g MMF组中，MPA Cmax与MPA - AUC(0 - 12)之间观察到可接受的相关性（r2为0.626至0.759）。观察到MPA浓度与IMPDH活性呈负相关。一般来说，给药后1小时至2小时达到MPA的最大浓度，IMPDH的最大抑制也在给药后1小时至2小时。IMPDH活性评估表明，0至1小时（P = 0.008）和0至2小时（P = 0.04）的样本之间存在显著统计学差异。总之，每天两次给予0.75 g和0.5 g的肾移植受者的浓度 - 时间曲线略低于2 g组，但差异不显著。另一方面，三组中IMPDH活性的抑制相当，表明个体间药效学存在相当大的变异性。免疫抑制程度的药效学监测及其与MPA血浆浓度的相关性将在未来研究中进一步评估。
