Abstract

1. Acetaminophen is gaining importance as a first-line drug for treating patent ductus arteriosus (PDA) in neonates. Predominant metabolites of acetaminophen in preterm neonates vary from that of adults; and the drug is predominantly metabolised by conjugation and partly by Cytochrome P450 (CYP) enzymes.

2. We carried out the present study to identify the principal urine metabolites of acetaminophen (glucuronide/sulphate) in preterm neonates with hemodynamically significant PDA receiving intravenous acetaminophen, and to evaluate the prevalence of single nucleotide polymorphisms (SNPs) in the key CYP enzymes (CYP1A2*3, CYP1A2*4, CYP1A2*1C, CYP1A2*1K, CYP1A2*6, CYP2D6*10, CYP2E1*2, CYP2E1*5B, CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A5*3, CYP3A5*7, and CYP3A5*11) and their effect on urinary metabolites and serum acetaminophen concentrations.

3. Nineteen (32.8%) neonates had heterozygous CYP1A2*1C, two (3.3%) with heterozygous CYP1A2*1K, 15 (27.8%) and two (3.7%) had heterozygous and homozygous CYP2D6*10, two (3.7%) had heterozygous CYP2E1*5B, seven (12.3%) and three (5.3%) had heterozygous and homozygous CYP3A4*1B, and three (5.5%) had CYP3A5*7 amongst the study population. Acetaminophen sulphate predominated over glucuronide metabolite at all time points. Postnatal days of life was significantly associated with an increase in the urine acetaminophen metabolites with decreased serum acetaminophen concentrations.

4. A significant prevalence of SNPs in the key CYP enzymes related to acetaminophen metabolism was observed in our neonatal population. Population pharmacokinetic-pharmacodynamic modelling incorporating genetic and metabolite data is urgently needed for implementation of precision medicine in this vulnerable population.

摘要

1. 对乙酰氨基酚作为治疗新生儿动脉导管未闭 (PDA) 的一线药物越来越重要。早产儿对乙酰氨基酚的主要代谢物与成人不同；该药物主要通过结合代谢，部分通过细胞色素 P450 (CYP) 酶进行代谢。

2. 我们开展了本研究，以确定接受静脉注射对乙酰氨基酚的血流动力学显着的 PDA 早产新生儿中对乙酰氨基酚（葡萄糖醛酸苷/硫酸盐）的主要尿液代谢物，并评估关键 CYP 酶（CYP1A2*）中单核苷酸多态性 (SNP) 的流行率3、CYP1A2*4、CYP1A2*1C、CYP1A2*1K、CYP1A2*6、CYP2D6*10、CYP2E1*2、CYP2E1*5B、CYP3A4*1B、CYP3A4*2、CYP3A4*3、CYP3A4*3、CYP3A*3和CYP3A5*11）及其对尿代谢物和血清对乙酰氨基酚浓度的影响。

3. 19 名 (32.8%) 新生儿CYP1A2*1C杂合，2 名 (3.3%) CYP1A2*1K杂合，15 名 (27.8%) 和 2 名 (3.7%) CYP2D6*10杂合和纯合，2 名 (3.7%) 杂合CYP2E *5B，在研究人群中，七名 (12.3%) 和三名 (5.3%) 具有杂合子和纯合子CYP3A4*1B，三名 (5.5%) 具有CYP3A5*7。在所有时间点，对乙酰氨基酚硫酸盐均优于葡萄糖醛酸代谢物。出生后的生命天数与尿对乙酰氨基酚代谢物的增加以及血清对乙酰氨基酚浓度的降低显着相关。

4. 在我们的新生儿人群中观察到与对乙酰氨基酚代谢相关的关键 CYP 酶中 SNP 的显着流行。迫切需要结合遗传和代谢物数据的群体药代动力学-药效学建模，以在这一弱势群体中实施精准医疗。