Ginsberg Gary, Hattis Dale, Miller Richard, Sonawane Babasaheb
Connecticut Department of Public Health, Hartford, Connecticut 06134, USA.
Pediatrics. 2004 Apr;113(4 Suppl):973-83.
Pharmacology and toxicology share a common interest in pharmacokinetic data, especially as it is available in pediatric populations. These data have been critical to the clinical pharmacologist for many years in designing age-specific dosing regimens. Now they are being used increasingly by toxicologists to understand the ontogeny of physiologic parameters that may affect the metabolism and clearance of environmental toxicants. This article reviews a wide range of physiologic and metabolic factors that are present in utero and in early postnatal life and that can affect the internal dose of an absorbed chemical and its metabolites. It also presents a child/adult pharmacokinetic database that includes data for 45 therapeutic drugs organized into specific children's age groupings and clearance pathways. Analysis of these data suggests that substantial child/adult differences in metabolism and clearance are likely for a variety of drugs and environmental chemicals in the early postnatal period. These results are also relevant to in utero exposures, where metabolic systems are even more immature, but exposures are greatly modified by the maternal system and placental metabolism. The implications of these child/adult differences for assessing children's risks from environmental toxicants is discussed with special focus on physiologically based pharmacokinetic modeling strategies that could simulate children's abilities to metabolize and eliminate chemicals at various developmental stages.
药理学和毒理学都对药代动力学数据有着共同的兴趣，尤其是儿科人群中的此类数据。多年来，这些数据对于临床药理学家设计针对特定年龄的给药方案至关重要。现在，毒理学家越来越多地利用这些数据来了解可能影响环境毒物代谢和清除的生理参数的个体发育情况。本文综述了子宫内和出生后早期存在的多种生理和代谢因素，这些因素会影响吸收的化学物质及其代谢产物的体内剂量。文章还展示了一个儿童/成人药代动力学数据库，其中包含45种治疗药物的数据，这些数据按照特定的儿童年龄分组和清除途径进行了整理。对这些数据的分析表明，出生后早期，多种药物和环境化学物质在代谢和清除方面很可能存在显著的儿童/成人差异。这些结果也与子宫内暴露相关，在子宫内，代谢系统更为不成熟，但暴露情况会受到母体系统和胎盘代谢的极大影响。本文讨论了这些儿童/成人差异对于评估儿童环境毒物风险的意义，特别关注基于生理学的药代动力学建模策略，该策略可模拟儿童在不同发育阶段代谢和消除化学物质的能力。
