Holford, N.H.
http://repub.eur.nl/ppl/13226/
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RePub, Erasmus University RepositoryDevelopmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children
http://repub.eur.nl/pub/10292/
Thu, 01 Jan 2004 00:00:01 GMT<div>Bouwmeester, J.</div><div>Anderson, B.J.</div><div>Tibboel, D.</div><div>Holford, N.H.</div>
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.