Uptake and excretion of sodium taurocholate by the isolated perfused neonatal sheep liver

Gow, Paul J; Treepongkaruna, Sa-ard; Ching, Michael S.; Ghabrial, Hany; Shulkes, Arthur; Smallwood, Richard A.; Jin, Chun Ji; Morgan, Denis J.

doi:10.1021/js9803151

Cited by 3 publications

(9 citation statements)

References 15 publications

(17 reference statements)

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“…The hepatic extraction ratio of the bile salt taurocholate was greater in the neonatal liver (0.56) (Gow et al 1999) than in the foetal liver (0.29) (Ring et al 1994) although extraction is even higher in the adult liver in a number of species (e.g. 0.85 in the rat, Klaassen & Watkins 1984;Smallwood et al 1988).…”

Section: Drug Elimination By the Perfused Neonatal Livermentioning

confidence: 98%

“…Studies have primarily involved the rat (Gores et al 1986) but have also included the human (Villeneuve et al 1990(Villeneuve et al , 1996, sheep (Linzell et al 1971) and rabbit (Bortolotti et al 1991;Corada et al 1992). We established the isolated perfused foetal sheep liver model (Ring et al 1994) and subsequently extended this technique to perfusion of the neonatal liver (Gow et al 1999). These models preserve the structural and functional integrity of the liver, circumvent the confounding elements of drug elimination by other organs, allow access to hepatic inflow, outflow and biliary tree, and readily permit hepatic extraction to be corrected for ductus venosus shunt.…”

Section: Drug Elimination By the Perfused Neonatal Livermentioning

confidence: 99%

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Neonatal Hepatic Drug Elimination

Gow

Ghabrial

Smallwood

et al. 2001

Pharmacology & Toxicology

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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: Drug Elimination By the Perfused Neonatal Livermentioning

confidence: 98%

Section: Drug Elimination By the Perfused Neonatal Livermentioning

confidence: 99%

Neonatal Hepatic Drug Elimination

Gow

Ghabrial

Smallwood

et al. 2001

Pharmacology & Toxicology

Self Cite

104

View full text Add to dashboard Cite

show abstract

“…These parameters are in keeping with our previous experience with this preparation. 8 The parameters did not change significantly over the experimental period, indicating stability and viability of the preparation. The mean liver weight was 114.7 ± 24.7 g, and ductus venosus flow as a proportion of total perfusate flow was 7.9 ± 8.1% (range, 0.0-18.2%) ( Table 1).…”

Section: Liver Viability and Stabilitymentioning

confidence: 90%

“…8 Anesthesia was induced in the neonatal sheep with halothane and thiopental. A midline abdominal incision was performed and cannulas were then inserted into the portal vein (inflow cannula), suprahepatic inferior vena cava (outflow cannula), and common bile duct.…”

Section: Recirculating Perfusion Of Isolated Neonatal Livermentioning

confidence: 99%

“…1 We have recently developed an analogous model with the neonatal liver that allows direct comparison of a variety of hepatic functions between the fetus and neonate. 8 In this study we have investigated the disposition of propranolol in the early neonatal sheep liver over a range of ages between 6 h and 10 days and compared the results with those previously obtained with the perfused near-term fetal sheep liver.…”

Section: Introductionmentioning

confidence: 99%

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