Acetaminophen: Potentially Toxic Metabolite Formed by Human Fetal and Adult Liver Microsomes and Isolated Fetal Liver Cells

Rollins, DE; Bahr, C von; Glaumann, Hans; Moldéus, Peter; Rane, Anders

doi:10.1126/science.38505

Cited by 117 publications

(50 citation statements)

References 16 publications

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“…The ability of human foetal hepatocytes to catalyse production of the toxic paracetamol oxidative metabolite, Nacetylbenzoquinoneimine (NAPQI), has been examined by Rollins et al (1979). The formation of NAPQI (measured as the GSH conjugate) by foetal hepatocytes was one-tenth of that compared with the adult level, and sulfation of paracetamol clearly predominated over glucuronidation in the foetus.…”

Section: Paracetamolmentioning

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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Section: Paracetamolmentioning

confidence: 99%

Neonatal Hepatic Drug Elimination

Gow

Ghabrial

Smallwood

et al. 2001

Pharmacology & Toxicology

104

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“…The metabolism of drugs by children is different from that of adults (Rane & Wilson, 1976;Rane, 1989), with age dependent differences for drugs that undergo oxidation (phenytoin, theophylline) as well as for drugs that undergo conjugation (oxazepam) (Tomson et al, 1979). A decreased ability to conjugate paracetamol with glucuronic acid, with increased conjugation to paracetamol sulphate has been reported in prepubertal children (Miller et al, 1976) and in foetal liver preparations (Rollins et al, 1979).…”

Section: Introductionmentioning

confidence: 99%

Morphine metabolism in children.

Choonara

McKay

Hain

et al. 1989

Brit J Clinical Pharma

141

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1 The metabolism of morphine was studied in 12 children and nine premature neonates on a continuous infusion of morphine (10-360 ,g kg-' h-1). 2 The mean plasma clearance of morphine was significantly higher in children than neonates (25.7 and 4.7 ml min-' kg-', respectively) (P < 0.01). 3 All the neonates and children had detectable concentrations of morphine-3-glucuronide (M3G) in plasma. All the children and five neonates had detectable concentrations of morphine-6-glucuronide (M6G) in plasma or urine. 4 The M3G/morphine ratios in plasma and urine, and M6G/morphine ratios in urine were significantly higher in children than neonates (P < 0.01), suggesting that morphine glucuronidation capacity is enhanced after the neonatal period. 5There was no difference in the M3G/M6G ratio in children and neonates, indicating a parallel development of both glucuronidation pathways.

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“…The capacity for glucuronidation of morphine is less in neonates in comparison with older children (Choonara et al, 1989). Studies with paracetamol have shown reduced glucuronidation with increased sulphation in neonates and infants (Miller et al, 1976), and conjugation by sulphation alone in human fetal hepatocytes (Rollins et al, 1979).…”

Section: Introductionmentioning

confidence: 99%

Morphine sulphation in children.

Choonara

Ekbom

Lindström

et al. 1990

Brit J Clinical Pharma

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The metabolism of morphine was studied in nine children and seven preterm neonates receiving a continuous infusion of morphine. All the neonates and three children had detectable concentrations of morphine-3-sulphate (M3S) in urine. None of the neonates or the children had detectable concentrations of morphine-6-sulphate (M6S) in urine. None of the children had detectable concentrations of M3S in plasma. The M3S/morphine ratios were significantly higher in neonates than children (P < 0.01), suggesting that morphine sulphation decreases after the neonatal period. The amount of M3S formed, even in neonates, is low suggesting that this is a minor metabolic pathway.

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Acetaminophen: Potentially Toxic Metabolite Formed by Human Fetal and Adult Liver Microsomes and Isolated Fetal Liver Cells

Cited by 117 publications

References 16 publications

Neonatal Hepatic Drug Elimination

Neonatal Hepatic Drug Elimination

Morphine metabolism in children.

Morphine sulphation in children.

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