Metabolism and Toxicity of Acetaminophen in Preterm Infants

对乙酰氨基酚在早产儿中的代谢和毒性

• 批准号: 7849339
• 负责人: JOHANNES NICOLAAS VAN DEN ANKER
• 金额: $ 34.45万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-10 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849339
• 关键词: Accounting; Acetaminophen; Address; Adolescent; Adoption; Adult; Adverse event; Age; Analgesics; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Biological Availability; Biological Markers; Child; Clinical; Clinical Pharmacology; Clinical Trials; Country; Data; Development; Dose; Drug Formulations; Drug Kinetics; Drug Metabolic Detoxication; Drug usage; Elderly; Enzymes; European; Exposure to; FDA approved; Future; Genes; Genetic Variation; Genotype; Glomerular Filtration Rate; Glucuronides; Glucuronosyltransferase; Goals; Growth; Hepatic; Human; Imines; Infant; Inorganic Sulfates; Intervention; Intravenous; Investigation; Kidney; Knowledge; Label; Liver Failure; Measurement; Measures; Medical; Medicine; Metabolic Biotransformation; Metabolism; N-acetyl-4-benzoquinoneimine; Neonatal; Neonatal Intensive Care Units; Newborn Infant; Opioid; Opioid Analgesics; Oral; Outcome; Pain; Pain management; Parents; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacology; Phase; Phenotype; Plasma; Population; Population Research; Premature Infant; Probability; Process; Proteins; Recording of previous events; Renal clearance function; Research Design; Research Proposals; Role; Safety; Serum; Staging; Sulfhydryl Compounds; Testing; Therapeutic; Time; Toxic effect; Transferase; Unspecified or Sulfate Ion Sulfates; Urine; Variant; Vulnerable Populations; acetaminophen overdose; adduct; base; cell injury; cytotoxicity; design; enzyme activity; experience; gastrointestinal; genetic association; improved; metabolomics; neonate; novel; p-Benzoquinones; para-benzoquinone; postnatal; premature; public health relevance; rectal; sulfotransferase

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.

描述（由申请人提供）：认识到早产儿会经历疼痛，并且充分的疼痛管理可以改善短期和长期结局，这导致疼痛控制物质在这一脆弱人群中的使用更加普遍。最近，阿片类药物相关不良事件的认识不断提高，促使对乙酰氨基酚（APAP）用于治疗早产儿疼痛的使用增加。然而，与足月婴儿、儿童和成人相比，关于APAP在早产新生儿中的代谢和潜在毒性的发育方面的可用信息少得多。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过量相关，甚至在成人治疗性暴露于APAP后也会发生。为了提高APAP在早产儿中使用的安全性和有效性，需要更好地了解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的测量结合代谢组学分析以及尿液和血清代谢组学来鉴定毒性相关的药物代谢物谱或新的生物标志物，将提供与评估APAP在早产儿中的安全性相关的新信息。本申请中提出的临床研究具有以下目的：1.评价发育阶段（定义为妊娠期和出生后年龄）与UDP-葡萄糖醛酸基转移酶1A 6（UGT 1A 6）和磺基转移酶1A 1（SULT 1A 1）活性的关系。2.评价早产儿不同发育阶段（按胎龄和出生后年龄测量）肾小球滤过率与对乙酰氨基酚（APAP）、APAP-葡萄糖醛酸苷和APAP-硫酸盐清除率的关系。3.评估UGT 1A 6基因型与UGT 1A 6表型的关系，以及SULT 1A 1基因型与SULT 1A 1表型的关系。4.评价发育阶段（由胎龄和出生后年龄定义）与APAP相关毒性（通过APAP-CYS和其他新型APAP毒性相关生物标志物的形成测量）的关系以及与累积APAP剂量的组合关系。 公共卫生相关性：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，尽管APAP是美国肝衰竭的主要原因。为了确保APAP在这一弱势人群中的安全使用，本研究计划将调查发育对早产儿代谢和APAP毒性的影响。