Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznan, Poland.
Department of Paediatric Nephrology and Hypertension, Poznan University of Medical Sciences, Poznan, Poland.
Clin Exp Pharmacol Physiol. 2022 Nov;49(11):1197-1208. doi: 10.1111/1440-1681.13706. Epub 2022 Aug 29.
Some studies have shown that the area under the concentration-time curve (AUC) of mycophenolic acid (MPA) should be higher for children with nephrotic syndrome (NS) than after renal transplantation. The pharmacodynamic aspect of MPA, the activity of inosine monophosphate dehydrogenase (IMPDH), has not been studied in children with NS. The study included 21 children (4-16 years old) with NS treated with mycophenolate mofetil. MPA and its glucuronide plasma concentrations were determined using validated high-performance liquid chromatography-ultraviolet (HPLC-UV). The separate HPLC-UV method was applied for IMPDH activity determination. The variability was expressed by the coefficient of variation (CV). IMPDH activity and MPA concentration (C ) before the morning dose amounted to 29.95 μmol s mol adenosine monophosphate (AMP) (range, 6.71-98.60 μmol s mol AMP) and 1.72 μg/mL (range, 0.39-4.34 μg/mL), respectively, whereas the area under the effect-time curve from 0 to 4 h and MPA AUC were 130.36 μmol s mol AMP × h (range, 23.58-306.57 μmol s mol AMP × h) and 24.63 μg h/mL (range, 12.21-67.48 μg h/mL), respectively. IMPDH activity decreased concomitantly with MPA concentration increase, however, the variability of the pharmacodynamic parameters was greater than of the pharmacokinetics. The median degree of maximum IMPDH inhibition was 61%. MPA C and predicted AUC were lower than in our previous study. Only a few MPA pharmacokinetic parameters correlated with the pharmacodynamics. IMPDH activity did not correlate with the children's age and did not differ between boys and girls. MPA clearance was the highest in younger children (median, 10.54 L/m /h) and cholesterol correlated negatively with the children's age (r = -0.659, P = 0.003). IMPDH minimum activity and the degree of maximum IMPDH inhibition were similar to those obtained in renal transplant recipients. IMPDH activity does not undergo developmental or gender-specific regulation in children with NS. MPA underexposure might be more frequent in younger children, especially with high cholesterol and triglycerides levels because of high MPA clearance.
一些研究表明，肾病综合征（NS）儿童的麦考酚酸（MPA）浓度-时间曲线下面积（AUC）应高于肾移植后。MPA 的药效学方面，即肌苷单磷酸脱氢酶（IMPDH）的活性，尚未在 NS 儿童中进行研究。该研究纳入了 21 名（4-16 岁）接受吗替麦考酚酯治疗的 NS 儿童。使用经过验证的高效液相色谱-紫外（HPLC-UV）法测定 MPA 和其葡萄糖醛酸血浆浓度。应用单独的 HPLC-UV 方法测定 IMPDH 活性。变异性用变异系数（CV）表示。早上剂量前的 IMPDH 活性和 MPA 浓度（C）分别为 29.95μmol·s·mol 腺嘌呤单磷酸（AMP）（范围为 6.71-98.60μmol·s·mol AMP）和 1.72μg/mL（范围为 0.39-4.34μg/mL），而 0 至 4 小时的效应时间曲线下面积和 MPA AUC 分别为 130.36μmol·s·mol AMP×h（范围为 23.58-306.57μmol·s·mol AMP×h）和 24.63μg·h/mL（范围为 12.21-67.48μg·h/mL）。IMPDH 活性随 MPA 浓度的增加而降低，但药效学参数的变异性大于药代动力学参数。最大 IMPDH 抑制程度的中位数为 61%。MPA C 和预测 AUC 低于我们之前的研究。只有少数 MPA 药代动力学参数与药效学相关。IMPDH 活性与儿童年龄无关，且男孩和女孩之间无差异。MPA 清除率在年龄较小的儿童中最高（中位数为 10.54L/m 2/h），胆固醇与儿童年龄呈负相关（r=-0.659，P=0.003）。IMPDH 最低活性和最大 IMPDH 抑制程度与肾移植受者相似。NS 儿童的 IMPDH 活性不受发育或性别特异性调节。MPA 低暴露可能在年龄较小的儿童中更为常见，尤其是胆固醇和甘油三酯水平较高的儿童，因为 MPA 清除率较高。
