A longitudinal study of cytochrome P450 2D6 (CYP2D6) activity during adolescence.
A longitudinal study of cytochrome P450 2D6 (CYP2D6) activity during adolescence.
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DOI：
10.1111/cts.13380
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发表时间：
2022-10
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CYP 2D 6底物是青少年中最常用的处方药之一，也通常与严重不良事件相关。为了研究青春期遗传变异、生长和发育对CYP 2D 6活性的相对贡献，入组时7-15岁的健康儿童和青少年参加了一项纵向表型研究，该研究涉及0.3 mg/kg美沙芬（DM）给药和每6个月采集4 h尿液，持续3年（共7次访视）。在每次访视时，记录身高、体重和性成熟度，并将CYP 2D 6活性测定为DM与其代谢物右啡烷（DX）的尿摩尔比。共有188名参与者完成了至少一次访视，102名参与者完成了所有七次研究访视。单变量分析后，只有CYP 2D 6活性评分（p < 0.001）、尿pH值（p < 0.001）、体重（p = 0.018）和注意缺陷多动障碍（ADHD）诊断（p < 0.001）与log（DM/DX）显著相关。具有随机截距、随机斜率协方差结构的线性混合模型分析结果显示，CYP 2D 6活性评分对log（DM/DX）的影响最强，弱代谢者的模型估计平均log（DM/DX）比活性评分3的患者高3.8 SD。性别对log（DM/DX）有中度影响，ADHD诊断和尿pH值对log（DM/DX）的影响较小。log（DM/DX）随年龄或青春期发育没有显著变化。CYP 2D 6基因型仍然是青春期CYP 2D 6活性变异性的单一、最大决定因素。鉴于CYP 2D 6底物在该儿童年龄组中的普遍使用，应考虑纳入基于基因型的给药指南。
CYP2D6 substrates are among the most highly prescribed medications in teenagers and also commonly associated with serious adverse events. To investigate the relative contributions of genetic variation, growth, and development on CYP2D6 activity during puberty, healthy children and adolescents 7–15 years of age at enrollment participated in a longitudinal phenotyping study involving administration of 0.3 mg/kg dextromethorphan (DM) and 4‐h urine collection every 6 months for 3 years (7 total visits). At each visit, height, weight, and sexual maturity were recorded, and CYP2D6 activity was determined as the urinary molar ratio of DM to its metabolite dextrorphan (DX). A total of 188 participants completed at least one visit, and 102 completed all seven study visits. Following univariate analysis, only CYP2D6 activity score (p < 0.001), urinary pH (p < 0.001), weight (p = 0.018), and attention‐deficit/hyperactivity disorder (ADHD) diagnosis (p < 0.001) were significantly correlated with log(DM/DX). Results of linear mixed model analysis with random intercept, random slope covariance structure revealed that CYP2D6 activity score had the strongest effect on log(DM/DX), with model‐estimated average log(DM/DX) being 3.8 SDs higher for poor metabolizers than for patients with activity score 3. A moderate effect on log(DM/DX) was observed for sex, and smaller effects were observed for ADHD diagnosis and urinary pH. The log(DM/DX) did not change meaningfully with age or pubertal development. CYP2D6 genotype remains the single, largest determinant of variability in CYP2D6 activity during puberty. Incorporation of genotype‐based dosing guidelines should be considered for CYP2D6 substrates given the prevalent use of these agents in this pediatric age group.
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发表时间：
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影响因子：
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DOI：
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发表时间：
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期刊：
CPT: pharmacometrics & systems pharmacology
影响因子：
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