Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, 295 Chipeta Way, Suite 1S100, Salt Lake City, UT, 84108, USA.
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 30 S 2000 E, Salt Lake City, UT, USA.
Clin Pharmacokinet. 2018 Oct;57(10):1325-1336. doi: 10.1007/s40262-018-0634-9.
Acetaminophen (paracetamol, APAP) is widely used as an analgesic and antipyretic drug in children and neonates. A number of enzymes contribute to the metabolism of acetaminophen, and genetic factors might be important to explain variability in acetaminophen metabolism among individuals.
The current investigation utilized a previously published parent-metabolite population pharmacokinetic model describing acetaminophen glucuronidation, sulfation, and oxidation to examine the potential role of genetic variability on the relevant metabolic pathways. Neonates were administered 30-min intravenous infusions of acetaminophen 15 mg/kg every 12 h (< 28 weeks' gestational age [GA]) or every 8 h (≥ 28 weeks GA) for 48 h. A total of 18 sequence variations (SVs) in UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), and cytochrome P450 (CYP) genes from 33 neonates (aged 1-26 days) were examined in a stepwise manner for an effect on the metabolic formation clearance of acetaminophen by glucuronidation (UGT), sulfation (SULT), and oxidation (CYP). The stepwise covariate modeling procedure was performed using NONMEM version 7.3.
Incorporation of genotype as a covariate for one SV located in the UGT1A9 gene promoter region (rs3832043, - 118 > insT, T > T) significantly improved model fit (likelihood ratio test, p < 0.001) and reduced between-subject variability in glucuronide formation clearance. Individuals with the UGT1A9 T polymorphism, indicating insertion of an additional thymidine nucleotide, had a 42% reduction in clearance to APAP-glucuronide as compared to their wild-type counterparts.
This study shows a pharmacogenetic effect of an SV in the UGT1A9 promoter region on the metabolism of acetaminophen in neonates.
醋氨酚（扑热息痛，APAP）被广泛用作儿童和新生儿的镇痛和退热药物。许多酶参与醋氨酚的代谢，遗传因素可能对个体间醋氨酚代谢的变异性很重要。
本研究利用以前发表的父母-代谢物群体药代动力学模型来描述醋氨酚的葡萄糖醛酸化、硫酸化和氧化，以研究遗传变异对相关代谢途径的潜在作用。新生儿在 48 小时内，每 12 小时（<28 周胎龄[GA]）或每 8 小时（≥28 周 GA）接受 15 毫克/公斤的静脉滴注 30 分钟。对 33 名年龄在 1-26 天的新生儿的 UDP-葡萄糖醛酸转移酶（UGT）、磺基转移酶（SULT）和细胞色素 P450（CYP）基因中的 18 个序列变异（SVs）进行了逐步检查，以研究其对醋氨酚葡萄糖醛酸化（UGT）、硫酸化（SULT）和氧化（CYP）代谢形成清除率的影响。使用 NONMEM 版本 7.3 逐步进行协变量建模程序。
将基因型作为 UGT1A9 基因启动子区域（rs3832043，-118 > insT，T > T）中一个 SV 的协变量纳入模型显著改善了模型拟合（似然比检验，p < 0.001），并降低了葡萄糖醛酸形成清除率的个体间变异性。与野生型相比，UGT1A9 T 多态性（表明插入了一个额外的胸苷核苷酸）个体的 APAP-葡萄糖醛酸清除率降低了 42%。
本研究表明 UGT1A9 启动子区域中的 SV 对新生儿醋氨酚代谢具有遗传药理学作用。
