Morphine metabolism in children.

Choonara, I A; McKay, Paulina; Hain, Richard; Rane, Anders

doi:10.1111/j.1365-2125.1989.tb03548.x

Cited by 141 publications

(79 citation statements)

References 31 publications

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“…Hence, it is likely that 6-acetylmorphine does enhance the analgesic effect of morphine, and, because of its higher lipid solubility compared with morphine, is more likely to cross the blood-brain barrier rapidly in the premature infant and induce a faster onset of analgesia than morphine. Studies in adults have confirmed that morphine-6-glucuronide, a major metabolite of morphine (Figure 1), also has significant analgesic activity (Osborne et al, 1988) though a recent study failed to detect this compound in neonatal plasma after morphine administration (Choonara et al, 1989). Hence, there is a complex relationship between these three pharmacologically active metabolites which will determine the degree of analgesia produced by diamorphine.…”

Section: Discussionmentioning

confidence: 99%

Morphine kinetics after diamorphine infusion in premature neonates.

Barrett

Elias-Jones

Rutter

et al. 1991

Brit J Clinical Pharma

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1 The pharmacokinetics of morphine were studied in 26 newborn premature neonates (26-38 weeks gestational age) who were given a loading dose of 50 pLg kg-' of diamorphine followed by an intravenous infusion of 15 ,ug kg-' h-1 of diamorphine.Plasma concentrations of morphine were measured during the infusion at steady-state and for 24 h after the cessation of the diamorphine infusion. 2 The mean steady-state plasma morphine concentration (± s.d.) for a diamorphine infusion rate of 15 ,ug kg-' h-1 was 62.5 ± 22.8 ng ml-'.3 Morphine clearance was 3.6 ± 0.9 ml min-' kg-1, the elimination half-life was 8.93.3 h and the volume of distribution was 2.7 ± 1.0 1 kg-'. 4 Morphine elimination kinetics were described by a mono-exponential function. 5There was a direct relationship between the gestational age of the patients and the clearance (r2 = 0.31, P = 0.003) and half-life (r2 = 0.35, P = 0.01) of morphine, but no relationship was found between gestational age and volume of distribution. 6 The results suggest that the currently used dosing regimen of diamorphine achieves a safe and effective morphine concentration in the premature newborn but that the loading dose could be modified to achieve a more rapid onset of analgesia.Keywords diamorphine morphine pharmacokinetics premature newborn intravenous infusion dose regimen

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Section: Discussionmentioning

confidence: 99%

Morphine kinetics after diamorphine infusion in premature neonates.

Barrett

Elias-Jones

Rutter

et al. 1991

Brit J Clinical Pharma

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“…The absence of morphine in two patients may reflect a genetic inability to carry out this reaction. Neonates (Choonara et al, 1987) and newborns (Lynn & Slattery, 1987) appear to have a reduced capability of forming the glucuronide conjugates of morphine. The sulphation of morphine is more marked in neonates than in children but it is a minor pathway (Choonara et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Infants and young children metabolise codeine to morphine. A study after single and repeated rectal administration.

Quiding

Olsson

Boréus

et al. 1992

Brit J Clinical Pharma

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1 Codeine was administered rectally to thirteen infants and young children undergoing elective surgery. Nine infants (6-10 months old) received a 4 mg suppository and four children (3-4 years old) an 8 mg suppository. Codeine and its metabolite morphine were measured in plasma by GC/MS. 2 The mean concentrations of codeine at 3, 4 and 5 h after administration were 240, 163and 123 nmol 1-1 in the younger and 309, 251 and 169 nmol 1-1 in the older patients.The corresponding concentrations of morphine were 8.3, 7.4 and 4.5 nmol l-1 and 6.8, 5.5 and 2.8 nmol l-1 respectively. One patient in each age group had no detectable amounts of morphine. 3 In the four children, the rectal dose was repeated 6-hourly for four doses. The plasma concentrations of codeine and morphine following the fifth dose were similar to those after the first dose. The mean AUC(0,5 h) of morphine was 1.6% that of codeine. 4 In the infants the mean plasma half-lives of codeine and morphine were 2.6 and 2.5 h.The two infants with the lowest body weights had the longest half-lives. 5 The mean morphine/codeine concentration ratio was 4.3% in the infants and 1.6% in the children, suggesting impaired glucuronidation of morphine in the former group. The hourly concentration ratios were almost identical following the first and fifth dose in the children. 6 We conclude that at the age of 6 months infants are capable of O-demethylating codeine to morphine.

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“…However, studies of morphine pharmacokinetics in the neonate have exhibited wide variability in results, particularly in premature infants and in the first week of life. Some glucuronidation of morphine MiniReview has been found even in the very premature neonate of 24-25 weeks gestational age (Choonara et al 1989). In three studies in premature neonates of gestational age 25-36 weeks, mean clearance ranged from 2.2-2.8 ml/min./kg (Chay et al 1992;Hartley et al 1993;Mikkelsen et al 1994).…”

Section: Morphinementioning

confidence: 99%

“…It has been proposed that the plasma morphine-3-glucuronide/morphine ratio provides a useful index of glucuronidation in the presence of normal renal function (Choonara et al 1989). Reported values were 5.0 in nine premature neonates, 8.0 in six full-term neonates, compared with 23.9 in nine children ages 1-16 years.…”

Section: Morphinementioning

confidence: 99%

Neonatal Hepatic Drug Elimination

Gow

Ghabrial

Smallwood

et al. 2001

Pharmacology & Toxicology

104

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After the transition from in utero to newborn life, the neonate becomes solely reliant upon its own drug clearance processes to metabolise xenobiotics. Whilst most studies of neonatal hepatic drug elimination have focussed upon in vitro expression and activities of drug-metabolising enzymes, the rapid physiological changes in the early neonatal period of life also need to be considered. There are dramatic changes in neonatal liver blood flow and hepatic oxygenation due to the loss of the umbilical blood supply, the increasing portal vein blood flow, and the gradual closure of the ductus venosus shunt during the first week of life. These changes which may well affect the capacity of neonatal hepatic drug metabolism. The hepatic expression of cytochromes P450 1A2, 2C, 2D6, 2E1 and 3A4 develop at different rates in the postnatal period, whilst 3A7 expression diminishes. Hepatic glucuronidation in the human neonate is relatively immature at birth, which contrasts with the considerably more mature neonatal hepatic sulfation activity. Limited in vivo studies show that the human neonate can significantly metabolise xenobiotics but clearance is considerably less compared with the older infant and adult. The neonatal population included in pharmacological studies is highly heterogeneous with respect to age, body weight, ductus venosus closure and disease processes, making it difficult to interpret data arising from human neonatal studies. Studies in the perfused foetal and neonatal sheep liver have demonstrated how the oxidative and conjugative hepatic elimination of drugs by the intact organ is significantly increased during the first week of life, highlighting that future studies will need to consider the profound physiological changes that may influence neonatal hepatic drug elimination shortly after birth.The development of clinical pharmacology has resulted in a more rational approach to drug therapy, as well as a deeper understanding of the factors capable of influencing drug disposition, and hence drug effects. Of these factors, age is of great importance. However, substantial differences in drug disposition not only exist between neonates and adults, but also among premature neonates, term neonates, infants and children.During the last two decades drug disposition in the neonatal period has been studied extensively. A major impetus for these studies seems to have been a series of incidents involving illness or death following the administration of drugs at ratios of dose/body weight innocuous in an adult (Craft et al. 1974;Gershanik et al. 1982). These studies have shown that the transition from neonate to childhood is characterised by the ontogeny of all of the processes of drug absorption, distribution, hepatic metabolism and renal excretion, with the development of hepatic drug metabolism being particularly important.The extent to which the neonatal drug-metabolising en-

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Morphine metabolism in children.

Cited by 141 publications

References 31 publications

Morphine kinetics after diamorphine infusion in premature neonates.

Morphine kinetics after diamorphine infusion in premature neonates.

Infants and young children metabolise codeine to morphine. A study after single and repeated rectal administration.

Neonatal Hepatic Drug Elimination

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