Prausa S E, Fukuda T, Maseck D, Curtsinger K L, Liu C, Zhang K, Nick T G, Sherbotie J R, Ellis E N, Goebel J, Vinks A A
Division of Pharmacy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Clin Pharmacol Ther. 2009 May;85(5):495-500. doi: 10.1038/clpt.2009.3. Epub 2009 Feb 18.
Leukopenia and diarrhea are the predominant adverse events associated with mycophenolate mofetil (MMF), leading to dose reduction or discontinuation in children. Polymorphisms of the drug's main metabolizing enzyme, uridine diphosphate-glucuronosyl transferase (UGT), confer alteration in drug exposure. We studied the incidence of these polymorphisms in pediatric kidney transplant recipients experiencing MMF-associated leukopenia and diarrhea. UGT genotypes of 16 affected children who recovered after MMF dose reduction or discontinuation were compared with those of 22 children who tolerated the drug at standard doses. DNA was extracted and sequenced using standard procedures to detect polymorphisms associated with increased (e.g., UGT1A9 -331T>C) or decreased drug exposure. All three patients who were homozygous for UGT1A9 -331T>C developed leukopenia, and heterozygotes also had significantly more toxicity (P = 0.04). A weaker association (P = 0.08) existed in UGT2B7 -900G>A carriers. Our data implicate UGT polymorphisms associated with altered drug exposure as potential predictors of MMF adverse events.
白细胞减少和腹泻是与霉酚酸酯（MMF）相关的主要不良事件，会导致儿童减量或停用该药物。该药物主要代谢酶尿苷二磷酸葡萄糖醛酸转移酶（UGT）的多态性会导致药物暴露量改变。我们研究了发生MMF相关白细胞减少和腹泻的儿科肾移植受者中这些多态性的发生率。将16名在MMF减量或停药后康复的受影响儿童的UGT基因型与22名接受标准剂量药物治疗且耐受的儿童的UGT基因型进行比较。使用标准程序提取DNA并进行测序，以检测与药物暴露增加（例如，UGT1A9 -331T>C）或减少相关的多态性。所有3名UGT1A9 -331T>C纯合子患者均出现白细胞减少，杂合子的毒性也明显更高（P = 0.04）。UGT2B7 -900G>A携带者的相关性较弱（P = 0.08）。我们的数据表明，与药物暴露改变相关的UGT多态性可能是MMF不良事件的潜在预测指标。
