Development of CYP2D6 and CYP3A4 in the First Year of Life

  title={Development of CYP2D6 and CYP3A4 in the First Year of Life},
  author={Trevor N Johnson and Geoffrey T Tucker and Amin Rostami-Hodjegan},
  journal={Clinical Pharmacology \& Therapeutics},
methadone requirements. We agree that further research is required to investigate this discrepancy between the observations of the two studies, particularly with patient groups receiving comparable daily doses of methadone. In addition, the clinical usefulness of other markers, such as plasma concentrations and pharmacodynamic responses to methadone, should also be considered as a more appropriate reflection of how much methadone is reaching the site of action, as opposed to a daily dose which… 

Maturation of cytochrome P450 3A mediated drug metabolism: Towards individualized dosing in children

Most drugs have not been adequately studied in children, leaving this population at an increased risk of underdosing or toxicity, and an increase in the number of studies investigating long-term effects, i.e. neurodevelopmental outcome in children.

Developmental Pharmacogenetics of CYP2D6 in Chinese Children: Loratadine as a Substrate Drug

The developmental pharmacogenetics of CYP2D6 in Chinese children was evaluated using loratadine as a substrate drug to evaluate the effects of ontogeny and pharmacogenetic profiles in people of different ancestries.

Developmental Changes in the Expression and Function of Cytochrome P450 3A Isoforms: Evidence from In Vitro and In Vivo Investigations

Innovative study methods, including opportunistic sampling and sensitive analytical assays used in combination with physiologically based pharmacokinetics, and population pharmacokinetic model concepts may help to improve the understanding of the ontogeny of CYP3A and aid the application of this knowledge in clinical practice.

Developmental pharmacokinetics.

Application of novel technologies in the fields of pharmacometrics, pharmacogenomics and biomarker development, and pharmacodynamic surrogate endpoints suitable for pediatric use are increasingly making integrated approaches for developmentally appropriate dose regimen selection possible.

Ontogeny of Drug-Metabolizing Enzymes.

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Drug metabolism in early infancy: opioids as an illustration

It is suggested that researchers should not continue to develop new models, but should investigate whether collected data fit in already existing models and provide additional value concerning the impact of (non)-maturational factors like drug-drug interactions or pharmacogenetics.

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Ontogeny of Dextromethorphan O‐ and N‐demethylation in the First Year of Life

Genotype and the temporal acquisition of drug biotransformation are critical determinants of a drug response in infants and a strong correlation between CYP2D6 genotype and DM O‐demethylation was indicated.

In-vivo indices of enzyme activity: the effect of renal impairment on the assessment of CYP2D6 activity.

The application of the analysis to the experimental data indicates that CYP2D6 activity is compromised in parallel with deterioration of renal function and no consistent behaviour of this index is expected when markers with different pharmacokinetics are used.

Expression of CYP2D6 in developing human liver.

The rise in CYP2D6 protein was associated with the developmental onset of dextromethorphan O-dem methylation, but not N-demethylation, even if activity was lower in fetal than in neonatal and in adult liver microsomes, suggesting that regulation is primarily at the transcriptional level, but cannot rule out the participation of post-transcriptional events in the regulation process throughout ontogenesis.

Assessment of In Vivo CYP2D6 Activity: Differential Sensitivity of Commonly Used Probes to Urine pH

Without control of urine pH, in vivo estimates of CYP2D6 metabolic activity are likely to be less precise using DM or MP as probe substrates compared to DB, which may contribute to difficulties in differentiating in vivo metabolic activity among allelic variants within the overall CYP1D6 EM phenotype.

Prediction of the Clearance of Eleven Drugs and Associated Variability in Neonates, Infants and Children

The in silico prediction of pharmacokinetic behaviour in paediatric patients is not intended to replace clinical studies, however, it provides a valuable aid to decision-making with regard to first-time dosing in children and study design.

Stereoselective Block of hERG Channel by (S)‐Methadone and QT Interval Prolongation in CYP2B6 Slow Metabolizers

This study reports the first genetic factor implicated in methadone metabolism that may increase the risk of cardiac arrhythmias and sudden death and could be reduced by the administration of (R)‐methadone.

Drug‐Induced Torsades de Pointes and Implications for Drug Development

A consensus is reached by an independent academic task force on the physiologic understanding of drug‐induced repolarization changes, their preclinical and clinical evaluation, and the risk‐to‐benefit interpretation of drug-induced torsades de pointes.

Problems of Heart Rate Correction in Assessment of Drug‐Induced QT Interval Prolongation

  • M. Malik
  • Medicine
    Journal of cardiovascular electrophysiology
  • 2001
A strategy for heart rate correction in drug safety studies is proposed and the strategy is demonstrated using a study of ebastine, a nonsedating antihistamine.