Department of Paediatrics I, University Children's Hospital Heidelberg, Heidelberg, Germany.
Eur J Clin Pharmacol. 2012 Jun;68(6):913-22. doi: 10.1007/s00228-011-1203-4. Epub 2012 Jan 25.
Since many drug targets and metabolizing enzymes are developmentally regulated, we investigated a potential comparable regulation of inosine 5'-monophosphate dehydrogenase (IMPDH) activity that has recently been advocated as a pharmacodynamic biomarker of mycophenolic acid (MPA) effects in the paediatric population. Since the field of pharmacodynamic monitoring of MPA is evolving, we also analyzed the response of IMPDH activity on MPA in children vs adolescents after renal transplantation.
We analyzed IMPDH activity in peripheral blood mononuclear cells (PBMCs) in 79 healthy children aged 2.0-17.9 years in comparison to 106 healthy adults. Pharmacokinetic/pharmacodynamic profiles of MPA and IMPDH over 6 or 12 h after mycophenolate mofetil dosing were performed in 17 paediatric renal transplant recipients. IMPDH activity was measured by HPLC and normalized to the adenosine monophosphate (AMP) content of the cells, MPA plasma concentrations were measured by HPLC.
Inosine 5'-monophosphate dehydrogenase activity displayed a high inter-individual variability (coefficient of variation 40.2%) throughout the entire age range studied. Median IMPDH did not differ significantly in healthy pre-school children (82 [range, 42-184] μmol/s/mol AMP), school-age children (61 [30-153]), adolescents (83 [43-154]) and healthy adults (83 [26-215]). Similar to adults, IMPDH activity in children and adolescents was inversely correlated with MPA plasma concentration.
In conclusion, our data do not show a pronounced developmental regulation of IMPDH activity in PBMCs in the paediatric population and there is a comparable inhibition of IMPDH activity by MPA in children and adolescents after renal transplantation.
由于许多药物靶点和代谢酶都受发育调控，我们研究了肌苷 5'-单磷酸脱氢酶（IMPDH）活性的潜在可比调控，该酶最近被提倡作为儿童人群中霉酚酸（MPA）作用的药效动力学生物标志物。由于 MPA 药效动力学监测领域正在不断发展，我们还分析了儿童和青少年肾移植后 MPA 对 IMPDH 活性的影响。
我们分析了 79 名年龄在 2.0-17.9 岁的健康儿童和 106 名健康成年人外周血单核细胞（PBMC）中的 IMPDH 活性。在 17 名接受麦考酚酸酯的儿科肾移植受者中进行了 MPA 和 IMPDH 在 6 或 12 小时后的药代动力学/药效动力学分析。通过 HPLC 测量 IMPDH 活性，并将其与细胞中腺嘌呤单磷酸（AMP）的含量归一化，通过 HPLC 测量 MPA 血浆浓度。
在整个研究年龄范围内，肌苷 5'-单磷酸脱氢酶（IMPDH）活性表现出高度的个体间变异性（变异系数 40.2%）。健康学龄前儿童（82 [范围 42-184] μmol/s/mol AMP）、学龄儿童（61 [30-153]）、青少年（83 [43-154]）和健康成年人（83 [26-215]）的中位数 IMPDH 无显著差异。与成人一样，儿童和青少年的 IMPDH 活性与 MPA 血浆浓度呈负相关。
总之，我们的数据并未显示儿科人群 PBMC 中 IMPDH 活性存在明显的发育调节，并且儿童和青少年肾移植后 MPA 对 IMPDH 活性具有可比的抑制作用。
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