Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children
Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children
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DOI：
10.1093/bja/aeh042
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发表时间：
2004-02-01
影响因子：
9.8
通讯作者：
Holford, NHG
中科院分区：
文献类型：
--
作者：
Bouwmeester, NJ;Anderson, BJ;Holford, NHG
背景关于吗啡及其代谢物在幼儿中的药代动力学和代谢的描述很少。以前的研究没有区分大小的影响，从那些与年龄在婴儿期。术后0-3岁的儿童静脉注射负荷剂量的盐酸吗啡（2分钟内100 μ g/kg），然后静脉输注10 μ g/h/kg（n=92）或每3小时静脉推注30 μ g/kg（n=92）。如果视觉模拟（VAS，0-10）疼痛评分大于或等于4，则每10分钟给予额外的吗啡（5 μ g kg（-1））。在负荷剂量给药后5 min内以及给药后6、12和24 h采集动脉血（1.4 ml），用于吗啡、吗啡-3-葡萄糖醛酸苷（M3 G）和吗啡-6-葡萄糖醛酸苷（M6 G）。采用非线性混合效应模型估计吗啡的处置和吗啡碱对其葡糖苷酸代谢产物的形成清除率及其消除清除率。该分析使用了184例受试者的1856个浓度观察值。单室一级消除模型的群体参数估计值及其变异性（%）如下：分布容积136（59.3）升，编队间隙至M3 G 64.3（58.8）升h（-1），编队间隙至M6 G 3.63（82.2）升h（-1），通过其他途径的吗啡清除率为3.12升h（-1）/70 kg，M3 G的消除清除率为17.4（43.0）升h（-1），M6 G的消除清除率为5.8（73.8）升h（-1）。使用异速生长3/4幂模型将所有参数标准化为70 kg的人，并反映完全成熟的成人值。分布容积呈指数增加，成熟半衰期为26天，出生时为83升/70 kg; M3 G和M6 G的形成清除率增加，成熟半衰期为88.3天，出生时分别为10.8和0.61升/70 kg。代谢产物的形成随着血清胆红素浓度的增加而减少。代谢物清除率随年龄增长而增加（成熟半衰期为129天），似乎与婴儿肾小球滤过率成熟的描述相似。M3 G是吗啡在幼儿中的主要代谢物，6个月时全身吗啡清除率为成人值的80%。在重症监护病房接受非心脏手术的儿童，出生时输注5 μ g·h-1·kg-1盐酸吗啡，可达到平均稳态血药浓度10 ng·ml-1（足月新生儿），1个月时为8.5 mug h（-1）kg（-1），3个月时为13.5 mug h（-1）kg（-1），1岁时为18 mug h（-1）kg（-1），1至3岁儿童为16 mug h（-1）kg（-1）。
Background. Descriptions of the pharmacokinetics and metabolism of morphine and its metabolites in young children are scant. Previous studies have not differentiated the effects of size from those related to age during infancy.Methods. Postoperative children 0-3 yr old were given an intravenous loading dose of morphine hydrochloride (100 mug kg(-1) in 2 min) followed by either an intravenous morphine infusion of 10 mug h(-1) kg(-1) (n=92) or 3-hourly intravenous morphine boluses of 30 mug kg(-1) (n=92). Additional morphine (5 mug kg(-1)) every 10 min was given if the visual analogue (VAS, 0-10) pain score was greater than or equal to4. Arterial blood (1.4 ml) was sampled within 5 min of the loading dose and at 6, 12 and 24 h for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The disposition of morphine and formation clearances of morphine base to its glucuronide metabolites and their elimination clearances were estimated using non-linear mixed effects models.Results. The analysis used 1856 concentration observations from 184 subjects. Population parameter estimates and their variability (%) for a one-compartment, first-order elimination model were as follows: volume of distribution 136 (59.3) litres, formation clearance to M3G 64.3 (58.8) litres h(-1), formation clearance to M6G 3.63 (82.2) litres h(-1), morphine clearance by other routes 3.12 litres h(-1) per 70 kg, elimination clearance of M3G 17.4 (43.0) litres h(-1), elimination clearance of M6G 5.8 (73.8) litres h(-1). All parameters are standardized to a 70 kg person using allometric 3/4 power models and reflect fully mature adult values. The volume of distribution increased exponentially with a maturation half-life of 26 days from 83 litres per 70 kg at birth; formation clearance to M3G and M6G increased with a maturation half-life of 88.3 days from 10.8 and 0.61 litres h(-1) per 70 kg respectively at birth. Metabolite formation decreased with increased serum bilirubin concentration. Metabolite clearance increased with age (maturation half-life 129 days), and appeared to be similar to that described for glomerular filtration rate maturation in infants.Conclusion. M3G is the predominant metabolite of morphine in young children and total body morphine clearance is 80% that of adult values by 6 months. A mean steady-state serum concentration of 10 ng ml(-1) can be achieved in children after non-cardiac surgery in an intensive care unit with a morphine hydrochloride infusion of 5 mug h(-1) kg(-1) at birth (term neonates), 8.5 mug h(-1) kg(-1) at 1 month, 13.5 mug h(-1) kg(-1) at 3 months and 18 mug h(-1) kg(-1) at 1 year and 16 mug h(-1) kg(-1) for 1- to 3-yr-old children.