Developmental expression of drug metabolizing enzymes: impact on disposition in neonates and young children

Area of Science:

• Pharmacology
• Developmental Biology
• Pediatric Medicine

Background:

• Drug metabolizing enzyme expression undergoes profound developmental changes, impacting drug efficacy and safety in neonates and young children.
• Hepatic drug metabolizing enzymes exhibit distinct developmental trajectories, categorized into three classes.
• Significant interindividual variability exists in the timing of these developmental changes, creating windows of hypervariability.

Purpose of the Study:

• To review current knowledge on drug metabolizing enzyme ontogeny during development.
• To highlight the interplay between developmental and genetic factors in pediatric drug disposition.
• To identify challenges in applying pharmacogenomics for pediatric drug safety.

Main Methods:

• Review of existing literature on drug metabolizing enzyme development.
• Categorization of enzymes based on developmental trajectories.
• Integration of developmental and genetic data into physiologically-based pharmacokinetic (PBPK) models.

Main Results:

• Drug metabolizing enzymes can be classified into three developmental categories.
• Perinatal changes in enzyme expression vary by enzyme and show significant interindividual timing differences.
• Developmental factors can outweigh pharmacogenetic influences in children.

Conclusions:

• Accurate prediction of pediatric drug metabolism requires integrating developmental and genetic data.
• Physiologically-based pharmacokinetic models are valuable tools for predicting age-dependent metabolic capacities.
• Addressing developmental variability is key to improving pediatric drug safety through pharmacogenomics.