Shaw L M, Mick R, Nowak I, Korecka M, Brayman K L
Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA.
J Clin Pharmacol. 1998 Mar;38(3):268-75. doi: 10.1002/j.1552-4604.1998.tb04424.x.
The pharmacokinetics of mycophenolic acid (MPA), the immunosuppressant form of the prodrug mycophenolate mofetil (MMF), and the primary glucuronide metabolite, MPAG, were characterized in renal transplant patients with delayed graft function using random effects piecewise linear models. Eight patients were evaluated after receiving their first and subsequent daily oral doses of 1.5 g mycophenolate mofetil twice daily on study days 1 (n = 8), 7 (n = 8), 14 (n = 5), 21 (n = 2), and 28 (n = 7). The area under the concentration-time curve from zero to 12 hours (AUC0-12) for MPA, MPAG, MPA free fraction, and free MPA were analyzed in serial plasma samples using validated high-performance liquid chromatography and ultrafiltration procedures. Random effects piecewise linear models, fit by maximum likelihood methods, were applied to AUC0-12 of MPA and MPAG, MPA free fraction, AUC0-12 of free MPA, and serum creatinine concentration, the index of renal function used in this study. Two hemodialysis sessions did not lower MPA plasma concentration, although some MPAG was removed. The AUC0-12 of MPA increased as a function of time, although it was not possible to fit a statistical model to the data due to considerable among-patient variation in the pattern of increase with time. The AUC0-12 of MPAG, MPA free fraction, and AUC0-12 of free MPA reached maximal values on day 7; each of these parameters had unique day 1 to 7 positive slope values and unique day 7 to 28 negative slope values. The average creatinine concentration was maximal at day 1 and a unique negative slope was obtained between days 7 and 28. Thus, this study provides statistical models for the alteration of AUC0-12 of MPAG, MPA free fraction, AUC0-12 of free MPA, and serum creatinine in renal transplant patients with delayed graft function. These results provide evidence that renal dysfunction is associated with altered pharmacokinetics of MPA, particularly increased AUC0-12 of MPAG, MPA free fraction, and AUC0-12 of free MPA. The perturbed pharmacokinetics normalized with improving renal function.
采用随机效应分段线性模型，对移植肾功能延迟的肾移植患者中麦考酚酸（MPA，前体药物吗替麦考酚酯（MMF）的免疫抑制形式）及其主要葡萄糖醛酸代谢产物MPAG的药代动力学进行了表征。在研究的第1天（n = 8）、第7天（n = 8）、第14天（n = 5）、第21天（n = 2）和第28天（n = 7），8名患者在首次及随后每日两次口服1.5 g吗替麦考酚酯后接受评估。使用经过验证的高效液相色谱法和超滤程序，对系列血浆样本中的MPA、MPAG、MPA游离分数和游离MPA从零至12小时的浓度-时间曲线下面积（AUC0-12）进行了分析。通过最大似然法拟合的随机效应分段线性模型应用于MPA和MPAG的AUC0-12、MPA游离分数、游离MPA的AUC0-12以及血清肌酐浓度（本研究中使用的肾功能指标）。两次血液透析虽清除了部分MPAG，但未降低MPA血浆浓度。MPA的AUC0-12随时间增加，尽管由于患者间随时间增加模式存在相当大的差异，无法对数据拟合统计模型。MPAG的AUC0-12、MPA游离分数和游离MPA的AUC0-12在第7天达到最大值；这些参数在第1至7天各有独特的正斜率值，在第7至28天各有独特的负斜率值。平均肌酐浓度在第1天最高，在第7至28天获得独特的负斜率。因此，本研究为移植肾功能延迟的肾移植患者中MPAG的AUC0-12、MPA游离分数、游离MPA的AUC0-12和血清肌酐的变化提供了统计模型。这些结果证明肾功能障碍与MPA药代动力学改变有关，特别是MPAG的AUC0-12、MPA游离分数和游离MPA的AUC0-12增加。药代动力学紊乱随肾功能改善而恢复正常。
