Naesens Maarten, de Loor Henriette, Vanrenterghem Yves, Kuypers Dirk R J
Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Catholic University of Leuven, Leuven, Belgium.
Transplantation. 2007 Aug 15;84(3):362-73. doi: 10.1097/01.tp.0000276936.14041.6c.
Previous studies have shown that total-body clearance of mycophenolic acid (MPA) is increased and total MPA exposure decreased in renal allograft recipients with severe renal dysfunction. In contrast to these studies, other studies have associated renal impairment with higher MPA exposure. The reason for these inconsistencies is not clear.
In 120 renal allograft recipients with stable graft function and treated with a combination of mycophenolate mofetil, tacrolimus, and corticosteroids, clinical determinants of exposure to total MPA and its glucuronide metabolite MPA 7-O-glucuronide (MPAG) were investigated in a multivariate regression model at 3 (n=118) and 12 (n=63) months after transplantation.
Almost 50% of total MPA exposure could be explained by the final model, in which proteinuria, glomerular filtration rate, diabetes mellitus, and the mycophenolate mofetil dose were independent determinants of total MPA exposure. Lower glomerular filtration rate (GFR) was independently associated with higher MPA exposure both at 3 and 12 months after transplantation. GFR, alanine aminotransferase, and serum albumin levels and mycophenolate mofetil dose explained 69% of total MPAG exposure variability.
In stable renal recipients, total MPA exposure negatively associates with renal function, through accumulation of both MPA and MPAG in patients with moderately reduced renal allograft function. This is in contrast to severe graft dysfunction, where MPA clearance is higher due to increased free fraction of MPA, as shown in previous studies. The duality in the effect of graft function on MPA pharmacokinetics is of clinical importance, adjusting mycophenolate mofetil dose according to renal function might help to avoid side effects and improve efficacy.
既往研究表明，严重肾功能不全的肾移植受者中，霉酚酸（MPA）的全身清除率增加，MPA的总体暴露量降低。与这些研究相反，其他研究发现肾功能损害与较高的MPA暴露有关。这些不一致的原因尚不清楚。
在120例移植肾功能稳定、接受霉酚酸酯、他克莫司和皮质类固醇联合治疗的肾移植受者中，采用多变量回归模型研究移植后3个月（n = 118）和12个月（n = 63）时MPA及其葡萄糖醛酸代谢产物MPA 7 - O - 葡萄糖醛酸（MPAG）暴露的临床决定因素。
最终模型可以解释近50%的MPA总暴露量，其中蛋白尿、肾小球滤过率、糖尿病和霉酚酸酯剂量是MPA总暴露量的独立决定因素。较低的肾小球滤过率（GFR）在移植后3个月和12个月均与较高的MPA暴露独立相关。GFR、丙氨酸转氨酶、血清白蛋白水平和霉酚酸酯剂量解释了69%的MPAG总暴露变异性。
在移植肾功能稳定的受者中，由于移植肾功能中度降低的患者中MPA和MPAG均蓄积，MPA总暴露量与肾功能呈负相关。这与严重移植功能障碍相反，如既往研究所示，严重移植功能障碍时MPA清除率较高是由于MPA游离分数增加。移植功能对MPA药代动力学影响的双重性具有临床重要性，根据肾功能调整霉酚酸酯剂量可能有助于避免副作用并提高疗效。
