Ontogeny of drug metabolizing enzymes in the neonate

Blake, Michael; Castro, Lisa; Leeder, J. Steven; Kearns, Gregory L.

doi:10.1016/j.siny.2004.11.001

Cited by 163 publications

(106 citation statements)

References 159 publications

Supporting

Mentioning

103

Contrasting

Unclassified

Order By: Relevance

“…A imaturidade fisiológica afeta a absorção e a distribuição de fármacos devido à composição dos compartimentos corporais e conteúdo de água, ligação de proteínas, fatores hemodinâmicos e metabolismo de drogas (clearance renal ou hepático) 21 . Exposição a múltiplos agentes é também um fator de aumento da incidência de eventos adversos em neonatos: muitas medicações podem ser incompatíveis ou interagir umas com as outras 22 .…”

Section: Discussionunclassified

Use of off-label and unlicensed drugs in the neonatal intensive care unit and its association with severity scores

Carvalho

Ribeiro²,

Bonilha³

et al. 2012

J Pediatr (Rio J)

View full text Add to dashboard Cite

Objective: To analyze the frequency of unlicensed (UL) and offlabel (OL) prescriptions in neonates admitted to the neonatal intensive care unit of a tertiary care hospital and to determine their association with patients' severity. Methods:Observational cohort study including drugs prescribed during hospitalization of neonates over a 6-week period between July and August 2011. The drugs were classified as UL and OL for dose, frequency, presentation, age group, or indication, according to an electronic list of drugs approved by the Food and Drug Administration. Patients were followed until hospital discharge or 31 days of hospitalization, with daily records of the Neonatal Therapeutic Intervention Scoring System (NTISS). Results:We identified 318 prescription items for 61 patients (average of five items/patient); there were only 13 patients with appropriate use of medications (21%). A prevalence of 7.5% was identified for UL prescriptions and 27.7% for OL, and the most prevalent OL use was that related to age group -19.5%. Fifty-seven medications were computedone patient received 10 UL/OL drugs during hospitalization. The prevalence of OL uses was higher in preterm infants < 35 weeks and in those with higher severity scores (p = 0.00). Conclusions:The prevalence of neonates exposed to UL/OL drugs during hospitalization was high, especially for those with higher NTISS scores. Although there is general appreciation that neonates, especially preterm infants, have a high rate of drug use, an assessment including different cultures and countries is still needed to prioritize areas for future research in the pharmacotherapy of this vulnerable population.J Pediatr (Rio J). 2012;88(6):465-70: Drugs, drug labeling, injury severity score, neonatology. ResumoObjetivo: Avaliar a frequência da prescrição de medicamentos de uso não licenciado (UL) e off-label (OL) em recém-nascidos internados em unidade de tratamento intensivo neonatal de hospital de nível terciário e verificar a associação do seu uso com a gravidade dos pacientes.Métodos: Estudo observacional de coorte dos medicamentos prescritos no período de 6 semanas da internação de neonatos, entre julho e agosto de 2011. Os medicamentos foram classificados em UL e OL para dose, frequência, apresentação, faixa etária e indicação, de acordo com bulário eletrônico aprovado pela Food and Drug Administration. Os pacientes foram acompanhados até alta hospitalar ou 31 dias de internação, com registro diário do Neonatal Therapeutic Intervention Scoring System. Resultados:Foram identificados 318 itens de prescrição para 61 pacientes (média de cinco itens/paciente) e apenas 13 pacientes com uso de medicamentos adequados (21%). Identificaram-se prevalên-cias de 7,5% para prescrições UL e de 27,7% para OL. O uso OL mais prevalente foi para medicamentos não padronizados para faixa etária -19,5%. Computaram-se 57 medicações -um paciente recebeu 10 fármacos UL/OL na internação. A prevalência de usos OL foi maior em prematuros < 35 semanas e nos com escores de gravidade mais ele...

show abstract

Section: Discussionunclassified

Use of off-label and unlicensed drugs in the neonatal intensive care unit and its association with severity scores

Carvalho

Ribeiro²,

Bonilha³

et al. 2012

J Pediatr (Rio J)

View full text Add to dashboard Cite

show abstract

“…Changes in expression of some phase-I enzymes during liver maturation in humans have been reported, including cytochrome P450 (P450) (Stevens et al, 2003(Stevens et al, , 2008Koukouritaki et al, 2004;Croom et al, 2009), carboxylesterase (CES) (Yang et al, 2009;Zhu et al, 2009), paraoxonase (PON) (Cole et al, 2003;Huen et al, 2009), alcohol dehydrogenase (ADH) (Smith et al, 1971), and flavin monooxygenase (FMO) (Cherrington et al, 1998;Koukouritaki et al, 2002;Hines, 2006). The dynamic changes in the ontogenic expression of these genes are thought to be responsible for the substantial pharmacokinetic differences between newborns and adults, and this contributes to differences in therapeutic efficacy and adverse drug reactions in pediatric patients (Kearns et al, 2003;Blake et al, 2005;Hines, 2007Hines, , 2008Hines, , 2013). An in-depth understanding of the regulatory mechanisms of the ontogeny of phase-I enzymes is needed for safer and more effective drug therapy for pediatric patients.…”

Section: Introductionmentioning

confidence: 99%

RNA-Sequencing Quantification of Hepatic Ontogeny of Phase-I Enzymes in Mice

et al. 2013

View full text Add to dashboard Cite

Phase-I drug metabolizing enzymes catalyze reactions of hydrolysis, reduction, and oxidation of drugs and play a critical role in drug metabolism. However, the functions of most phase-I enzymes are not mature at birth, which markedly affects drug metabolism in newborns. Therefore, characterization of the expression profiles of phase-I enzymes and the underlying regulatory mechanisms during liver maturation is needed for better estimation of using drugs in pediatric patients. The mouse is an animal model widely used for studying the mechanisms in the regulation of developmental expression of phase-I genes. Therefore, we applied RNA sequencing to provide a "true quantification" of the mRNA expression of phase-I genes in the mouse liver during development. Liver samples of male C57BL/6 mice at 12 different ages from prenatal to adulthood were used for defining the ontogenic mRNA profiles of phase-I families, including hydrolysis: carboxylesterase (Ces), paraoxonase (Pon), and epoxide hydrolase (Ephx); reduction: aldo-keto reductase (Akr), quinone oxidoreductase (Nqo), and dihydropyrimidine dehydrogenase (Dpyd); and oxidation: alcohol dehydrogenase (Adh), aldehyde dehydrogenase (Aldh), flavin monooxygenases (Fmo), molybdenum hydroxylase (Aox and Xdh), cytochrome P450 (P450), and cytochrome P450 oxidoreductase (Por). Two rapidly increasing stages of total phase-I gene expression after birth reflect functional transition of the liver during development. Diverse expression patterns were identified, and some large gene families contained the mRNA of genes that are enriched at different stages of development. Our study reveals the mRNA abundance of phase-I genes in the mouse liver during development and provides a valuable foundation for mechanistic studies in the future.

show abstract

“…It has been known since the 1950s that P450 enzymes are not mature at birth (Fouts and Adamson, 1959); however, at that time, it was thought that there was only one or perhaps two P450 enzymes. Since the cloning of the P450 genes, ontogenic expression of some P450 genes in human livers has been reported (de Wildt et al, 1999;Koukouritaki et al, 2004;Blake et al, 2005;Leeder et al, 2005;Gaedigk et al, 2006;Hines, 2007). Based on hepatic ontogenic gene expression patterns, human drug-metabolizing P450 genes have been categorized into three developmental patterns (Hines, 2007).…”

mentioning

confidence: 99%

Three Patterns of Cytochrome P450 Gene Expression during Liver Maturation in Mice

Hart¹,

Cui²,

Klaassen³

et al. 2008

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:The neonatal period of liver development is an often overlooked phase of development. For instance, ontogeny of xenobioticmetabolizing enzymes can markedly affect biotransformation as the liver matures. To systematically examine the ontogenic gene expression patterns of cytochrome P450 genes (P450) in mice, the gene expression profiles of 19 xenobiotic-metabolizing P450 in Cyp1 to 4 families were determined. The mRNA levels in C57BL/6 mouse livers were quantified using branched DNA technology at the following ages: gestational day 17 (2 days before birth) and postnatal days 0, 1, 3, 5, 10, 15, 20, 30, and 45. Among the 13 P450 genes expressed in mouse livers, three distinct ontogenic expression patterns were identified by cluster analysis. Genes in group 1 (Cyp3a16 as well as 3a41b in male) were expressed in the perinatal period, but they were essentially nondetectable by 30 days of age. Genes in group 2 (Cyp2e1, 3a11, and 4a10 as well as 3a41b in female) quickly increased after birth and reached maximal expression levels by day 5. Genes in group 3 (Cyp1a2, 2a4, 2b10, 2c29, 2d22, 2f2, 3a13, and 3a25) were expressed at low levels until days 10 to 15, but they markedly increased at day 20 to a high and stable level. In conclusion, the developmental expression of P450 in mouse liver can be divided into three patterns, suggesting that different mechanisms are responsible for the expression of P450 during liver maturation.

show abstract

Ontogeny of drug metabolizing enzymes in the neonate

Cited by 163 publications

References 159 publications

Use of off-label and unlicensed drugs in the neonatal intensive care unit and its association with severity scores

Use of off-label and unlicensed drugs in the neonatal intensive care unit and its association with severity scores

RNA-Sequencing Quantification of Hepatic Ontogeny of Phase-I Enzymes in Mice

Three Patterns of Cytochrome P450 Gene Expression during Liver Maturation in Mice

Contact Info

Product

Resources

About