Department of Biomedical and Pharmaceutical Sciences, Center for Pharmacogenomics and Molecular Therapy, University of Rhode Island, Kingston, RI 02881, USA.
J Infect Dis. 2011 Apr 1;203(7):937-42. doi: 10.1093/infdis/jiq145.
Oseltamivir, a widely used anti-influenza drug, is hydrolytically activated by carboxylesterase 1 (CES1). The expression of this carboxylesterase is developmentally regulated. This study was performed to determine when after birth infants acquire competence of activating this prodrug.
Liver tissue samples were collected and divided into 5 age groups: group 1 (1-31 d old), group 2 (35-70 d old), group 3 (89-119 d old), group 4 (123-198 d old), and group 5 (>18 years of age). These samples were analyzed for oseltamivir hydrolysis and CES1 expression.
Liver samples in group 1 expressed the lowest level of CES1 with the lowest hydrolytic activity toward oseltamivir. A 4-7-fold increase between groups 1 and 2 (1-31 vs 35-70 d of age) was detected in the hydrolysis and expression analyses, respectively. Liver samples in the other 3 pediatric groups (35-198 d of age) exhibited similar expression and hydrolysis levels. Overall, liver samples in group 1 had CES1 expression and hydrolysis levels that were 10% of those of adults, whereas liver samples in the other 3 pediatric groups had levels that were ∼50% of adult levels.
The post-neonatal surge in CES1 expression ensures the hydrolytic capacity to be gained rapidly after birth in infants, but the larger variability during this period suggests that caution should be exercised on the extrapolated dosing regimens of ester drugs from other age groups.
奥司他韦是一种广泛使用的抗流感药物,它通过羧酸酯酶 1(CES1)水解激活。这种羧酸酯酶的表达受发育调控。本研究旨在确定婴儿在出生后何时获得激活该前药的能力。
收集肝组织样本并分为 5 个年龄组:第 1 组(1-31 天)、第 2 组(35-70 天)、第 3 组(89-119 天)、第 4 组(123-198 天)和第 5 组(>18 岁)。分析这些样本的奥司他韦水解和 CES1 表达情况。
第 1 组肝组织样本表达的 CES1 水平最低,对奥司他韦的水解活性最低。第 1 组和第 2 组(1-31 天与 35-70 天)之间的水解和表达分析分别检测到 4-7 倍的增加。其他 3 个儿科年龄组(35-198 天)的肝组织样本表现出相似的表达和水解水平。总体而言,第 1 组肝组织样本的 CES1 表达和水解水平仅为成人的 10%,而其他 3 个儿科年龄组的水平为成人的 50%左右。
新生儿后期 CES1 表达的激增确保了婴儿出生后迅速获得水解能力,但在此期间的较大变异性表明,应谨慎对待从其他年龄组推断的酯类药物的外推给药方案。