Cytochrome P450 Genetic Polymorphism in Neonatal Drug Metabolism: Role and Practical Consequences towards a New Drug Culture in Neonatology

Abstract

The cytochrome P450 superfamily (CYP450) in humans is formed by 57 functional monooxygenases critical for the metabolism of numerous endogenous and exogenous compounds. The superfamily is organized into 18 families and 44 subfamilies. CYP nomenclature is based on the identity of amino acids. The most important functions of the CYP450 are related to metabolism of endogenous compounds, detoxification of exogenous xenobiotics and decomposition of the vast majority of currently used drugs. The expression of CYP450 enzymes in the human body is characterized by a marked substrate and tissue specificity, the most important being localized in the liver, but also present in kidney, lung, brain, breast, prostate and in the small intestine. The human cytochrome P450 3A gene family (CYP3A) accounts for the largest portion of CYP450 proteins in human liver and includes 4 genes: CYP3A4, CYP3A5, CYP3A7, CYP3A43. Multiple and complex genetic variations, marked interindividual, interethnic and gender variability have been reported regarding CYP3A isoform expression and activity. Multiple factors may affect CYP3A expression and activity, such as inducers like rifampicin, phenobarbital, 3-methylcholantrene, beta-naphtoflavone, and dexamethasone. The maturation of organ systems, paralleled by ontogeny of drug-metabolizing enzymes during fetal life and in the first months of postnatal life, surely exerts profound effects on drug disposition, probably being the predominant factor accounting for age-associated changes in drug clearance. In fact, drug dosage in the perinatal period represents a continuous challenge for neonatologists. The purpose of this article is to provide a brief review of the pharmacokinetic differences between neonates and adults, showing the peculiarities of liver CYP450-related drug metabolism in the perinatal period and at birth, and to report the toxic mechanisms of liver injury in neonates, due to the most frequently utilized drugs in NICU centers.Drug dosage in the perinatal period represents a continuous challenge for neonatologists, particularly for those involved in neonatal intensive care unit (NICU) centers. In fact, the maturation of organ systems, paralleled by ontogeny of drug-metabolizing enzymes during fetal life and in the first months of

Systemic Absorption of Cyclopentolate and Adverse Events After Retinopathy of Prematurity Exams

“…25,26 These variations in blood levels are clinically significant and indicate a need to determine possible genetic influences on metabolism of this drug. 17,39 Genes that influence the metabolism of anticholinergics have been identified, and it is possible that one or more of these candidate genes may contribute to our findings. 20,32,40–43 …”

Genomic technologies in neonatology

“…Лекарственная тера-пия в неонатальном периоде требует существенных улучшений, в первую очередь в сфере проведения клинических испытаний и разрешения применения ряда лекарственных препаратов у новорожденных. Зачастую неонатологи вынуждены использовать пре-параты, официально не разрешенные к применению у новорожденных, и экстраполировать дозы, приме-няемые у детей и взрослых [43]. Критически важной является интеграция знаний об анатомо-физиологи-ческих особенностях доношенных и недоношенных новорожденных, влиянии патологических состоя-ний, возрастозависимых изменениях, данных фар-макогенетики в клинические исследования.…”

Current perspective on pediatric pharmacogenomics

“…Since the enzymatic activity of certain drug metabolizing enzymes can vary as a function of age and due to numerous developmental and maturation processes, the ontology of those enzymes and the influence of genetic variants on their activity are essential for the accurate prediction of treatment response in children. [1][2][3][4] One of the biggest challenges to treatment in children is the first dose. Clinical essays are far more difficult to carry in children than in adults, and thus, this dose is usually extrapolated by applying scaling approaches to data acquired from dosing essays in adults.…”

“…CYP3A7 to CYP3A4 in neonates). [2][3][4] Recent studies demonstrated that genetically guided personalized therapy holds the promise to deliver a safer and more effective treatment in pediatric organ transplantation. [5,6] One well-described example is the dosing of Tacrolimus (TAC), an immunosuppressant used to reduce organ rejection both in pediatric and in adult patients.…”