吗啡及其代谢产物在新生儿、婴儿和幼儿中的发育药代动力学。
Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children.
作者信息
Bouwmeester N J, Anderson B J, Tibboel D, Holford N H G
机构信息
Department of Anaesthesiology and Paediatric Surgery, Sophia Children's Hospital, University Hospital Rotterdam, Dr Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands.
出版信息
Br J Anaesth. 2004 Feb;92(2):208-17. doi: 10.1093/bja/aeh042.
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 micro g kg(-1) in 2 min) followed by either an intravenous morphine infusion of 10 micro g h(-1) kg(-1) (n=92) or 3-hourly intravenous morphine boluses of 30 micro g kg(-1) (n=92). Additional morphine (5 micro g kg(-1)) every 10 min was given if the visual analogue (VAS, 0-10) pain score was >/=4. 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 micro g h(-1) kg(-1) at birth (term neonates), 8.5 micro g h(-1) kg(-1) at 1 month, 13.5 micro g h(-1) kg(-1) at 3 months and 18 micro g h(-1) kg(-1) at 1 year and 16 micro g h(-1) kg(-1) for 1- to 3-yr-old children.
背景
关于吗啡及其代谢产物在幼儿体内的药代动力学和代谢情况的描述较少。以往的研究没有区分婴儿期体型与年龄相关因素的影响。
方法
对0至3岁的术后儿童静脉注射负荷剂量的盐酸吗啡（2分钟内100μg/kg），随后分别给予10μg·h⁻¹·kg⁻¹的静脉吗啡输注（n = 92）或每3小时静脉推注30μg/kg的吗啡（n = 92）。如果视觉模拟评分（VAS，0至10）疼痛评分≥4，则每10分钟额外给予吗啡（5μg/kg）。在负荷剂量后5分钟内以及6、十二和24小时采集动脉血（1.4ml），检测吗啡、吗啡 - 3 - 葡糖苷酸（M3G）和吗啡 - 6 - 葡糖苷酸（M6G）。使用非线性混合效应模型估计吗啡的处置、吗啡碱向其葡糖苷酸代谢产物的生成清除率及其消除清除率。
结果
分析使用了来自184名受试者的1856次浓度观测值。单室一级消除模型的总体参数估计值及其变异性（%）如下：分布容积136（59.3）升，M3G的生成清除率64.3（58.8）升·h⁻¹，M6G的生成清除率3.63（82.2）升·h⁻¹，每70kg体重其他途径的吗啡清除率3.12升·h⁻¹，M3G的消除清除率17.4（43.0）升·h⁻¹，M6G的消除清除率5.8（73.8）升·h⁻¹。所有参数使用异速生长3/4幂模型标准化为70kg体重的人，反映完全成熟的成人值。分布容积从出生时每70kg体重83升开始以26天的成熟半衰期呈指数增加；M3G和M6G的生成清除率分别从出生时每70kg体重10.8和0.61升·h⁻¹开始以88.3天的成熟半衰期增加。代谢产物生成随血清胆红素浓度升高而降低。代谢产物清除率随年龄增加（成熟半衰期129天），且似乎与婴儿肾小球滤过率成熟情况相似。
结论
M3G是幼儿体内吗啡的主要代谢产物，到6个月时全身吗啡清除率为成人值的80%。在重症监护病房，出生时（足月儿）给予5μg·h⁻¹·kg⁻¹的盐酸吗啡输注、1个月时8.5μg·h⁻¹·kg⁻¹、3个月时13.5μg·h⁻¹·kg⁻¹、1岁时18μg·h⁻¹·kg⁻¹以及1至3岁儿童16μg·h⁻¹·kg⁻¹，非心脏手术后儿童可达到平均稳态血清浓度10ng/ml。
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