Pharmacokinetics of intravenously administered indomethacin in premature infants

Thalji, Amin; Carr, Ian; Yeh, T. F.; Raval, D.; Luken, Julie A.; Pildes, Rosita S.

doi:10.1016/s0022-3476(80)80445-8

Cited by 78 publications

(52 citation statements)

References 15 publications

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“…However, its use has also been associated with several adverse reactions including reduced renal function and hemorrhagic episodes (6,5,12). Despite the increased usage, little is known about the metabolism of the drug in infants (9,16,18,24,25). A recent study demonstrated that the elimination halflife of indomethacin (I) was considerably prolonged as compared to reported adults values and plasma clearance values were approximately 25% of the adult values (9).…”

Section: (mentioning

confidence: 99%

Indomethacin Metabolism in Isolated Neonatal and Fetal Rabbit Hepatocytes

et al. 1981

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SummaryMetabolism of indomethacin was examined in freshly isolated hepatocytes prepared by liver collagenase perfusion of fetal (28) and neonatal rabbits of 3,5, 10, 12, and 25 days of age. Initial cell viability was more than 90% and linear rates of metabolism were observed for up to 2 hr of incubation. Deacylation of indomethacin to desbenzoyl indomethacin showed a rapid increase early in postnatal development while microsomal 0-demethylation to desmethyl indomethacin was increased significantly only in the hepatocytes from 25-day-old rabbits. Glucuronide conjugates of indomethacin and indomethacin metabolites accounted for less than 8% of the total metabolites in hepatocytes from 25-day-old rabbits and less than 2% in the 3-to 5-day-old rabbits. The maturational development of indomethacin in metabolism may account for previously reported gestational dependent half-life of the drug in the premature infant (9). However, the factors that regulate development of indomethacin metabolism appear to be under more than one control system. SpeculationThe noted adverse effects from indomethacin in the premature infant suffering from patent ductus arteriosus probably results from drug accumulation. Several independent pathways of metabolism for indomethacin have been demonstrated and the differences in their postnatal maturation may cause considerable variation in the patient disposition of the drug. These variations are important in the consideration of drug therapy in the premature infant.Biologic immaturity and its influence on the varying disposition of drugs is a major source of concern in the treatment of neonates and premature infants. Despite only limited knowledge in this area an increasing number of drugs are being used in preterm and term infants for various cardiac and respiratory problems. Hence, it has become increasingly important to identify those mechanisms which modulate drug disposition during development to help provide better prediction of pharmacologic disposition of a given drug. Hepatocytes isolated by the collagenase perfusion method have been shown to be a useful addition to the methods for study of drug metabolism and toxicity. Substrates for microsomal monooxygeiase are actively metabolized in the hepatocyte without added cofactors and detoxification vathways are also functional (14). Thus the isolated hepatocyte p;ovidesJan integrated cellular model for study of drug metabolism since it retains the structural and functional properties of the intact cell. Billings et al. (4) demonstrated that metabolic rates for selected chemicals in isolated hepatocytes correlate well with in vivo rates of drug metabolism. Other investigators have demonstrated that the isolated hepatocyte is an excellent model to study early stages of hepatotoxicity and allows for determination of structure activity relation- 140(ships (19). This model for study of drug disposition thus compliments others such as the isolated perfused liver and purified enzymes systems which can provide information on, respectively, the role...

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Section: (mentioning

confidence: 99%

Indomethacin Metabolism in Isolated Neonatal and Fetal Rabbit Hepatocytes

et al. 1981

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“…The lack of sufficient evidence regarding this perceived risk may explain the lack of uniformity among academic programs regarding the maximum number of indomethacin courses that can be used for persistent PDA [1]. Indomethacin is a known vasoconstrictor and because of its prolonged half-life in premature infants, there is a possibility of cumulative adverse effects with multiple courses of indomethacin [27,29]. Although indomethacin has been previously shown to cause acute renal dysfunction, we found no evidence of persistent renal dysfunction as evaluated by creatinine levels at 34 weeks of PMA, strongly suggesting that acute renal dysfunction, if it occurs, is transient and reversible [14].…”

Section: Discussionmentioning

confidence: 99%

“…Postnatal indomethacin use is associated with intestinal perforation and acute renal dysfunction in premature infants [2,14]. More recently antenatal indomethacin has been associated with PVL in premature infants (Amin SB, in press).Indomethacin has a longer half-life in premature infants; this may lead to accumulation with multiple courses, with a theoretical risk of increasing the adverse effects with multiple exposures to indomethacin [27,29]. To date, the usefulness of a third course of indomethacin, specifically the response rate of PDA closure and associated effects on neonatal outcomes, has not been reported in the literature.…”

mentioning

confidence: 99%

“…Indomethacin has a longer half-life in premature infants; this may lead to accumulation with multiple courses, with a theoretical risk of increasing the adverse effects with multiple exposures to indomethacin [27,29]. To date, the usefulness of a third course of indomethacin, specifically the response rate of PDA closure and associated effects on neonatal outcomes, has not been reported in the literature.…”

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Multiple Courses of Indomethacin and Neonatal Outcomes in Premature Infants

2007

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The objective of this retrospective cohort study was to determine patent ductus arteriosus (PDA) closure rate with multiple short courses (three doses) of postnatal indomethacin and compare neonatal outcomes in infants who received two versus three courses of indomethacin for PDA closure. Infants <34 weeks' gestational age born between January 2000 and December 2004 at the University of Maryland Medical Center and who received two or more short courses of indomethacin were included. Outcome measures were ductal closure rate and neonatal outcomes. Of 61 infants who were identified to have received two or more courses of indomethacin, 26 infants closed their ductus after the second course (response rate, 42%). Of the 35 infants who failed ductal closure after two courses, 11 infants had their ductus ligated and 23 received a third course of indomethacin. Of 23 who received a third course, 10 closed their ductus (response rate, 43%). There was no significant difference in the incidence of chronic lung disease, severe retinopathy of prematurity, necrotizing enterocolitis, renal function, or mortality between infants who received two and those who received three courses of indomethacin. Infants exposed to three courses of indo-methacin had a statistically nonsignificant increased incidence of periventricular leukomalacia (p = 0.08; adjusted odds ratio = 4.8; 95% CI, 0.8-30) and remained in the hospital for a longer duration (p = 0.02) compared to infants exposed to two courses of indomethacin. We conclude that multiple courses of indomethacin may be associated with a ductal closure. However, the requirement for a third course may be associated with an increased risk of periventricular leukomalacia. Indomethacin, a potent inhibitor of prostaglandin synthesis, has been routinely used to treat patent ductus arteriosus (PDA) in premature infants [10,28]. However, approximately 20%-40% of premature infants have residual luminal flow or fail to close after the initial short course (three doses given every 12 h) of indomethacin [4,12,15,28]. If the ductus fails to close after the initial course of indomethacin, surgical ligation of PDA and additional indomethacin treatment are two available options for the management of persistent PDA [20,24]. It is not clear whether surgical ligation or multiple courses of indo-methacin should be the preferred treatment of PDA that fails to close after the initial short course of indomethacin [7,19,25]. The medical literature suggests that additional indomethacin treatment is unlikely to produce ductus closure for premature infants, if there is persistent Doppler evidence of ductal flow within 24 h after completion of the initial short course of indomethacin [17]. Contrary to this limited evidence, a recent survey of Neonatal Fellowship Program Directors in the United States reported that multiple courses of indomethacin, up to three, are commonly used for persistent PDA, after the initial course of indo-methacin [1]. This survey also reported that there is wide variation in the ma...

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“…Although studies are being carried out on the pharmacokinetics of drugs in human concepti and newborns (86)(87)(88)(89)(90)(91) Even if the initial biochemical and/or morphological event at the time of insult leading to the ultimate manifestation at term has not been established, pharmacokinetics is useful in evaluating dose-response curves; that is, the relationship of the incidence or severity of the toxic response to the dose administered to the maternal organism and the maternal and/or fetal concentration of the toxicant.…”

Section: Pharmacokinetics and Critical (Sensitive) Periods Of Developmentioning

confidence: 99%

Interagency Regulatory Liaison Group Workshop on Reproductive Toxicity Risk Assessment

1986

Environmental Health Perspectives

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Pharmacokinetics of intravenously administered indomethacin in premature infants

Cited by 78 publications

References 15 publications

Indomethacin Metabolism in Isolated Neonatal and Fetal Rabbit Hepatocytes

Indomethacin Metabolism in Isolated Neonatal and Fetal Rabbit Hepatocytes

Multiple Courses of Indomethacin and Neonatal Outcomes in Premature Infants

Interagency Regulatory Liaison Group Workshop on Reproductive Toxicity Risk Assessment

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