Kennedy Mary Jayne, Davis Daniel A, Smith Ned, Gaedigk Andrea, Pearce Robin E, Kearns Gregory L
Kosair Charities Pediatric Clinical Research Unit, Department of Pediatrics, School of Medicine, University of Louisville, Louisville, Kentucky 40202, USA.
Clin Ther. 2008 Sep;30(9):1687-99. doi: 10.1016/j.clinthera.2008.09.012.
Recombinant human growth hormone (r-hGH) is increasingly being used in children. Although growth hormone (GH) may alter the clearance of concomitantly administered medications, its effects on individual drug-metabolizing enzymes in children have not been characterized.
The goal of this study was to assess the activities of cytochrome P450 (CYP) 1A2, N-acetyltransferase 2, xanthine oxidase, and CYP2D6 in children with isolated idiopathic GH deficiency before and 3 and 6 months after initiation of r-hGH treatment.
This 6-month, prospective, longitudinal, open-label phenotyping study was conducted at 4 academic tertiary care centers within the Pediatric Pharmacology Research Unit network. Prepubertal or early pubertal children (4-14 years) with short stature and isolated idiopathic GH deficiency were enrolled. Patients were given 4 ounces of a cola beverage and 0.5 mg/kg of dextromethorphan (DM) before and 3 and 6 months after initiation of r-hGH treatment. Urine was collected for 8 hours after probe substrate administration, and enzyme activity was assessed using validatedcaffeine/metaboliteandDM/metabolitemolar ratios. Patients with a DM/dextrorphan molar ratio > or =0.3 were classified as poor metabolizers, and those with a ratio <0.3 were classified as extensive metabolizers. Anthropometric and biochemical responses were assessed at each visit. Blood was also obtained for determination of serum insulinlike growth factor-1 (IGF-1) levels and CYP2D6 genotype.
Fourteen patients (mean [SD] age, 11.5 [2.6] years [age range, 4.5-14.6 years]; 11 males, 3 females; 100% white; median height and weight, 131.8 cm and 29.2 kg, respectively) completed the 3 study visits. However, data from 2 patients were excluded from analysis due to procedural violations. In all patients, growth velocity and serum IGF-1 concentrations were significantly higher (P < 0.001) after r-hGH treatment (mean doses, 0.32 and 0.33 mg/kg per week at 3 and 6 months, respectively). However, molar ratio values did not significantly change after initiation of r-hGH.
In this study population of children with isolated idiopathic GH deficiency, no significant differences in caffeine/metabolite and DM/metabolite molar ratios were observed after initiation of r-hGH treatment.
重组人生长激素（r-hGH）在儿童中的应用越来越广泛。尽管生长激素（GH）可能会改变同时服用药物的清除率，但其对儿童个体药物代谢酶的影响尚未明确。
本研究旨在评估单纯性特发性生长激素缺乏症儿童在开始r-hGH治疗前以及治疗3个月和6个月后细胞色素P450（CYP）1A2、N-乙酰转移酶2、黄嘌呤氧化酶和CYP2D6的活性。
这项为期6个月的前瞻性、纵向、开放标签的表型研究在儿科药理学研究单位网络内的4个学术三级医疗中心进行。纳入青春期前或青春期早期（4 - 14岁）身材矮小且患有单纯性特发性生长激素缺乏症的儿童。在开始r-hGH治疗前、治疗3个月和6个月后，患者饮用4盎司可乐饮料，并服用0.5 mg/kg右美沙芬（DM）。给予探针底物后收集8小时尿液，使用经过验证的咖啡因/代谢物和DM/代谢物摩尔比评估酶活性。DM/右啡烷摩尔比≥0.3的患者被归类为代谢缓慢者，比值<0.3的患者被归类为代谢正常者。每次就诊时评估人体测量和生化反应。还采集血液用于测定血清胰岛素样生长因子-1（IGF-1）水平和CYP2D6基因型。
14名患者（平均[标准差]年龄，11.5[2.6]岁[年龄范围，4.5 - 14.6岁]；11名男性，3名女性；100%为白人；中位身高和体重分别为131.8 cm和29.2 kg）完成了3次研究访视。然而，由于操作违规，2名患者的数据被排除在分析之外。在所有患者中，r-hGH治疗后生长速度和血清IGF-1浓度显著升高（P < 0.001）（3个月和6个月时的平均剂量分别为每周0.32和0.33 mg/kg）。然而，开始r-hGH治疗后摩尔比值没有显著变化。
在本研究的单纯性特发性生长激素缺乏症儿童群体中，开始r-hGH治疗后，咖啡因/代谢物和DM/代谢物摩尔比没有显著差异。
