Metabolism and Toxicity of Acetaminophen in Preterm Infants

描述(申请人提供)：认识到早产儿会经历疼痛，充分的疼痛管理可以改善短期和长期结果，这导致在这一弱势群体中更普遍地使用止痛药物。最近，人们对阿片类药物相关不良事件的认识不断增加，促使扑热息痛(APAP)用于治疗早产儿疼痛的使用增加。然而，与足月儿、儿童和成人相比，关于早产儿新陈代谢的发育方面和APAP潜在毒性的信息要少得多。此外，最近的数据表明，血清中APAP-Cys(APAP毒性的特异性生物标志物)的升高不仅与严重的APAP过量有关，甚至与成人治疗性暴露APAP有关。为了提高早产儿应用APAP的安全性和有效性，有必要更好地了解APAP在这一脆弱人群中代谢和潜在毒性的年龄相关差异的发育和药物遗传学决定因素。APAP-CyS的测定结合代谢组学、尿液和血清代谢组学的使用来识别毒性相关的药物代谢物或新的生物标志物，将为评估早产儿APAP的安全性提供新的信息。本申请中提出的临床研究有以下目的：1.评估发育阶段(由孕龄和出生后年龄定义)与UDP-葡萄糖醛酸基转移酶1A6(UGT1A6)和磺基转移酶1A1(SULT1A1)活性的关系。2.探讨不同发育阶段早产儿肾小球滤过率与对乙酰氨基酚(APAP)、APAP-葡萄糖醛酸苷和APAP-硫酸盐清除的关系。3.探讨UGT1A6基因型与UGT1A6表型的关系，以及SULT1A1基因型与SULT1A1表型的关系。4.评估发育阶段(由孕龄和出生后年龄定义)与APAP相关毒性(通过APAP-Cys和其他新的APAP毒性相关生物标志物的形成来衡量)之间的关系，以及与APAP累积剂量的联合关系。 公共卫生相关性：尽管静脉注射对乙酰氨基酚(APAP)是美国肝功能衰竭的主要原因，但在未来几年，早产儿静脉注射对乙酰氨基酚(APAP)的使用将显著增加。为了确保APAP在这一脆弱人群中的安全使用，本研究计划将调查发育对早产儿APAP代谢和毒性的影响。

DESCRIPTION (provided by applicant): The recognition that pain is experienced by preterm infants and that adequate pain management can improve both short and long term outcomes has led to the more common use of pain controlling substances in this vulnerable population. Recently, an increasing appreciation for opioid-associated adverse events has prompted an increase in the use of acetaminophen (APAP) for treating pain in preterm neonates. However, there is far less information available concerning developmental aspects of metabolism and potential toxicity of APAP in preterm neonates as compared to full term infants, children and adults. In addition, very recent data have shown that elevations of APAP-CYS (a specific biomarker for APAP toxicity) in serum occur not only in association with severe APAP overdose but even, after therapeutic exposure of APAP in adults. In order to enhance the safety and efficacy of APAP use in preterm neonates, there is a need for an improved understanding of the developmental and pharmacogenetic determinants of age-associated differences in the metabolism and potential toxicity of APAP in this vulnerable population. The measurement of APAP-CYS combined with the use of metabolomic profiling and urine and serum metabolomics to identify toxicity-associated drug metabolite profiles or new biomarkers will provide new information pertinent to assessing the safety of APAP in preterm neonates. The clinical investigations proposed in this application have the following aims: 1. To evaluate the relationship of developmental stage (defined by both gestational, and postnatal age) to UDP-glucuronosyltransferase 1A6 (UGT1A6) and sulfotransferase 1A1 (SULT1A1) activity. 2. To evaluate the relationship of glomerular filtration rate to the elimination clearances of acetaminophen (APAP), APAP-glucuronide and APAP-sulphate, at different developmental stage (as measured by gestational and postnatal age) of the preterm neonate. 3. To evaluate the relationship of UGT1A6 genotype to UGT1A6 phenotype, and the relationship of SULT1A1 genotype to SULT1A1 phenotype. 4. To evaluate the relationship of developmental stage (defined by both gestational and postnatal age) to APAP-associated toxicities (as measured by the formation of APAP-CYS and other novel APAP toxicity- associated biomarkers) and the combined relationship to cumulative APAP dose. PUBLIC HEALTH RELEVANCE: The use of intravenous acetaminophen (APAP) in preterm infants will increase significantly in the coming years, despite the fact that APAP is the major cause of liver failure in the US. To assure safe use of APAP in this vulnerable population, this research proposal will investigate the impact of development on metabolism and toxicity of APAP in preterm infants.