Mulla H, Yakkundi S, McElnay J, Lutsar I, Metsvaht T, Varendi H, Nellis G, Nunn A, Duncan J, Pandya H, Turner M
Department of Pharmacy, University Hospitals of Leicester, Leicester, UK,
Pharm Res. 2015 Mar;32(3):1084-93. doi: 10.1007/s11095-014-1520-2. Epub 2014 Sep 19.
Systemic exposure to parabens in the neonatal population, in particular propyl-parabens (PPB), remains a concern. Blood concentrations and kinetics of methyl-parabens (MPB) and PPB were therefore determined in neonates receiving medicines containing these excipients.
A multi-centre, non-interventional, observational study of excipient-kinetics in neonates. 'Dried Blood Spot' samples were collected opportunistically at the same time as routine samples and the observations modelled using a non-linear mixed effects approach.
A total of 841 blood MPB and PPB concentration data were available for evaluation from 181 pre- and term-neonates. Quantifiable blood concentrations of MPB and PPB were observed in 99% and 49% of patients, and 55% and 25% of all concentrations were above limit of detection (10 ng/ml), respectively. Only MPB data was amenable to modelling. Oral bioavailability was influenced by type of formulation and disposition was best described by a two compartment model with clearance (CL) influenced by post natal age (PNA); CL PNA<21 days 0.57 versus CL PNA>21 days 0.88 L/h.
Daily repeated administration of parabens containing medicines can result in prolonged systemic exposure to the parent compound in neonates. Animal toxicology studies of PPB that specifically address the neonatal period are required before a permitted daily exposure for this age group can be established.
新生儿群体对 parabens（对羟基苯甲酸酯）尤其是对羟基苯甲酸丙酯（PPB）的全身暴露仍令人担忧。因此，对接受含有这些辅料药物的新生儿进行了对羟基苯甲酸甲酯（MPB）和PPB的血药浓度及动力学研究。
一项针对新生儿辅料动力学的多中心、非干预性观察研究。在采集常规样本的同时， opportunistically采集“干血斑”样本，并采用非线性混合效应方法对观察结果进行建模。
共获得181例早产儿和足月儿的841份MPB和PPB血药浓度数据用于评估。99%和49%的患者观察到可量化的MPB和PPB血药浓度，所有浓度中分别有55%和25%高于检测限（10 ng/ml）。只有MPB数据适合建模。口服生物利用度受剂型影响较大，处置过程最好用二室模型描述，清除率（CL）受出生后年龄（PNA）影响；PNA<21天的CL为0.57 L/h，PNA>21天的CL为0.88 L/h。
每日重复给予含parabens的药物可导致新生儿对母体化合物的全身暴露延长。在确定该年龄组的每日允许暴露量之前，需要进行专门针对新生儿期的PPB动物毒理学研究。
