Department of Pharmacy, Akita University Hospital, Akita, Japan.
Basic Clin Pharmacol Toxicol. 2010 Aug;107(2):631-6. doi: 10.1111/j.1742-7843.2010.00542.x. Epub 2010 Feb 2.
The risk of acute rejection in patients with higher exposure to mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), might be due to inosine 5'-monophosphate dehydrogenase (IMPDH) polymorphisms. The correlations with subclinical acute rejection, IMPDH1 polymorphisms and MPA exposure on day 28 post-transplantation were investigated in 82 Japanese recipients. Renal transplant recipients were given combination immunosuppressive therapy consisting of tacrolimus and 1.0, 1.5 or 2.0 g/day of MMF in equally divided doses every 12 hr at designated times. There were no significant differences in the incidence of subclinical acute rejection between IMPDH1 rs2278293 or rs2278294 polymorphisms (p = 0.243 and 0.735, respectively). However, in the high MPA night-time exposure range (AUC > 60 microg x h/ml and C(0 )> or = 1.9 microg/ml), there was a significant difference in the incidence of subclinical acute rejection between IMPDH1 rs2278293 A/A, A/G and G/G genotypes (each p = 0.019), but not the IMPDH1 rs2278294 genotype. In the higher daytime MPA exposure range, patients with the IMPDH1 rs2278293 G/G genotype also tended to develop subclinical acute rejection. In patients with the IMPDH rs2278293 A/A genotype, the risk of subclinical acute rejection episode tends to be low and the administration of MMF was effective. The risk of subclinical acute rejection for recipients who cannot adapt in therapeutic drug monitoring (TDM) of MPA seems to be influenced by IMPDH1 rs2278293 polymorphism. The prospective analysis of IMPDH1 rs2278293 polymorphism as well as monitoring of MPA plasma concentration after transplantation might help to improve MMF therapy.
在接受麦考酚酸（MPA）暴露量较高的患者中，急性排斥反应的风险可能与肌苷 5'-单磷酸脱氢酶（IMPDH）多态性有关。在 82 例日本受者中，研究了亚临床急性排斥反应、IMPDH1 多态性与移植后第 28 天 MPA 暴露的相关性。肾移植受者接受他克莫司联合免疫抑制治疗，在指定时间内每 12 小时给予 1.0、1.5 或 2.0 g/d 的吗替麦考酚酯，分为相等剂量。IMPDH1 rs2278293 或 rs2278294 多态性的亚临床急性排斥反应发生率无显著差异（分别为 p = 0.243 和 0.735）。然而，在高 MPA 夜间暴露范围（AUC > 60 μg x h/ml 和 C（0）≥ 1.9 μg/ml）中，IMPDH1 rs2278293 A/A、A/G 和 G/G 基因型的亚临床急性排斥反应发生率存在显著差异（分别为 p = 0.019），但 IMPDH1 rs2278294 基因型无差异。在较高的日间 MPA 暴露范围内，具有 IMPDH1 rs2278293 G/G 基因型的患者也易发生亚临床急性排斥反应。在具有 IMPDH rs2278293 A/A 基因型的患者中，亚临床急性排斥反应发作的风险趋于较低，且麦考酚酯的给药有效。对于不能适应 MPA 治疗药物监测（TDM）的受者，亚临床急性排斥反应的风险似乎受到 IMPDH1 rs2278293 多态性的影响。前瞻性分析 IMPDH1 rs2278293 多态性以及移植后 MPA 血浆浓度的监测可能有助于改善 MMF 治疗。
