Ontogeny and drug metabolism in newborns
In pediatric age and particularly in newborn infants the drug efficacy and safety are influenced by the growth and development on drug Absorption, Distribution, Metabolism and Excretion (ADME). Thanks to the fast development of pharmacogenomics and pharmacogenetics, the drug therapy promises to be adapted to the genetic profile of the individual, reducing considerably the side effects of drugs and increasing their efficacy. Interindividual variability in drug response is well known in both adults and children. Such a variability is multifactorial considering both intrinsic and extrinsic factors. Drug distribution in the neonate is influenced by a variety of age-dependent factors as a total body water content and distribution variations, role of drug transporters, blood/tissue protein binding, blood and tissue pH and perfusion. The development of enzymes involved in human metabolism were classified in 3 categories: 1) those expressed during the whole or part of the fetal period, but silenced or expressed at low levels within 1-2 years after birth; 2) those expressed at relatively constant levels throughout fetal development, but increased to some extent postnatally; and 3) those whose onset of expression can occur in the third trimester, but substantial increase is noted in the first 1-2 years after birth. Besides this intrinsic aspects influencing pharmacokinetics during the neonatal period there are other important events such as inborn or acquired diseases, environment and finally pharmacogenetics and pharmacogenomics. Thousands of deaths every years are caused by fatal drug reactions; among the potential causes there are not only the severity of the disease being treated, drug interactions, nutritional status, renal and liver functions, but also the inherited differences in drug metabolism and genetic polymorphism. Adverse drug reactions (ADRs) among pediatric patients have been shown to be three times more frequent than in adults. On August 2010 The National Institute of Child Health and Human Development (NICHD) addressed patient safety issues in the NICU, recognizing that to understand and prevent adverse events, systematic research and education in safety issues needed. From all these concepts in terms of ADME, pharmacogenetics (relative to a single gene) and pharmacogenomics (relative to many genes) it is becoming more evident the perspective of the new concept of individualized medicine. The goal of this should be to identify which group of patients responds positively, which patients are nonresponders and who experiences adverse reaction for the same drug and dose. The interindividual variability in response to any drug is mostly dependent on DNA sequence variations across the human genome, the haplotype map (HAPMAP). At present there is still a big distance beween the knowledge in genetic and the practical application to model the drug profile to the genetic/genomic profile of the single patient. In the neonatal period the effects of growth in the pharmacodynamic, processes can help optimizing the dosage of neonatal frequently used medicines, thereby, minimizing their toxicity and increasing their efficacy. It should be useful to create accurate dosage adjustments according to the week of development.
Available from: Michael J Rieder
- "It has been appreciated for some time that an important determinant of drug response in children is in fact developmentally-induced changes in drug disposition related to maturation of pathways involved in drug activation and clearance, with the more recent appreciation that the ontogeny of drug receptors and transporters may be key elements in determining drug response in children (Kearns et al., 2003; Neville et al., 2011; Dotta and Chukhlantseva, 2012). As an example, in the fetus CYP3A7 is an important driver of oxidative drug metabolism while there is very little CYP3A4 activity; after birth, the amount of CYP3A7 rapidly declines while the activity of CYP3A4 steadily increases (Kearns et al., 2003; Dotta and Chukhlantseva, 2012). Renal drug excretion in the fetus is markedly reduced compared to older children; at birth term infants have a third of the capacity for glomerular filtration on a surface-area corrected basis compared to children at a year of age (Dotta and Chukhlantseva, 2012). "
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ABSTRACT: Adverse drug reactions are a common and important complication of drug therapy in children. Over the past decade it has become increasingly apparent that genetically controlled variations in drug disposition and response are important determinants of adverse events for many important adverse events associated with drug therapy in children. While this research has been difficult to conduct over the past decade technical and ethical evolution has greatly facilitated the ability of investigators to conduct pharmacogenomic studies in children. Some of this research has already resulted in changes in public policy and clinical practice, for example in the case of codeine use by mothers and children. It is likely that the use of pharmacogenomics to enhance drug safety will first be realized among selected groups of children with high rates of drug use such as children with cancer, but it also likely that this research will be extended to other groups of children who have high rates of drug utilization and as well as providing insights into the mechanisms and pathophysiology of adverse drug reactions in children.
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ABSTRACT: The complex process of oral drug absorption is influenced by a host of drug and formulation properties as well as their interaction with the gastrointestinal environment in terms of drug solubility, dissolution, permeability and pre-systemic metabolism. For adult dosage forms the use of biopharmaceutical tools to aid in the design and development of medicinal products is well documented. This review considers current literature evidence to guide development of bespoke paediatric biopharmaceutics tools and reviews current understanding surrounding extrapolation of adult methodology into a paediatric population. Clinical testing and the use of in silico models were also reviewed. The results demonstrate that further work is required to adequately characterise the paediatric gastrointestinal tract to ensure that biopharmaceutics tools are appropriate to predict performance within this population. The most vulnerable group was found to be neonates and infants up to 6months where differences from adults were greatest.
Available from: Gabriel Arther Knudsen
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ABSTRACT: Tetrabromobisphenol A (TBBPA) is the brominated flame retardant with the largest production volume worldwide. NTP 2-year bioassays found TBBPA dose-dependent increases in uterine tumors in female Wistar Han rats; evidence of reproductive tissues carcinogenicity was equivocal in male rats. To explain this apparent sex-dependence, the disposition and toxicokinetic profile of TBBPA were investigated using female Wistar Han rats, as no data were available for female rats. In these studies, the primary route of elimination following [14C]-TBBPA administration (25, 250 or 1000 mg/kg) was in feces; recoveries in 72 h were 95.7 ± 3.5%, 94.3 ± 3.6% and 98.8 ± 2.2%, respectively (urine: 0.2-2%; tissues: <0.1). TBBPA was conjugated to mono-glucuronide and -sulfate metabolites and eliminated in the bile. Plasma toxicokinetic parameters for a 250 mg/kg dose were estimated based on free TBBPA, as determined by UV/radiometric-HPLC analyses. Oral dosing by gavage (250 mg/kg) resulted in a rapid absorption of compound into the systemic circulation with an observed Cmax at 1.5 h post-dose followed by a prolonged terminal phase. TBBPA concentrations in plasma decreased rapidly after an IV dose (25 mg/kg) followed by a long elimination phase. These results indicate low systemic bioavailability (F < 0.05), similar to previous reports using male rats. Elimination pathways appeared to become saturated leading to delayed excretion after a single oral administration of the highest dose (1000 mg/kg); no such saturation or delay was detected at lower doses. Chronic high exposures to TBBPA may result in competition for metabolism with endogenous substrates in extrahepatic tissues (e.g., SULT1E1 estrogen sulfation) resulting in endocrine disruption.
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