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Drug metabolism and disposition in children
M Strolin Benedetti1, E L Baltes
1UCB Pharma, 21 rue de Neuilly, 92003 Nanterre Cedex, France.
Insights
Pediatric drug absorption, distribution, metabolism, and excretion differ from adults due to maturational changes. Key factors include altered gastrointestinal function, protein binding, and enzyme activity, impacting pediatric pharmacokinetics.
Area of Science:
- Pharmacology
- Pediatric Medicine
- Drug Metabolism
Background:
- Drug disposition varies significantly between pediatric and adult populations.
- Understanding these pediatric-specific pharmacokinetic differences is crucial for safe and effective drug therapy.
Purpose of the Study:
- To review key maturational factors influencing drug absorption, distribution, metabolism, and excretion in pediatric patients.
- To highlight developmental changes in physiological and enzymatic processes affecting pharmacokinetics in children.
Main Methods:
- Literature review of studies examining pediatric drug metabolism and disposition.
- Analysis of maturational changes in gastrointestinal, protein binding, metabolic, and renal excretion pathways.
Main Results:
- Pediatric drug absorption is affected by gastric pH, emptying, transit time, and P-glycoprotein.
- Drug distribution is influenced by membrane permeability, protein binding, body composition, and blood flow.
- Metabolism differences involve Phase I (CYP enzymes) and Phase II (transferases) enzymes.
- Renal excretion differences are attributed to glomerular filtration and tubular secretion maturation.
Conclusions:
- Significant maturational changes in absorption, distribution, metabolism, and excretion pathways explain pediatric pharmacokinetic variability.
- Further research on developmental aspects of transporters like P-glycoprotein is warranted for pediatric drug development.
Abstract:
Key factors undergoing maturational changes accounting for differences in drug metabolism and disposition in the pediatric population compared with adults are reviewed. Gastric and duodenal pH, gastric emptying time, intestinal transit time, bacterial colonization and probably P-glycoprotein are important factors for drug absorption, whereas key factors explaining differences in drug distribution between the pediatric population and adults are membrane permeability, plasma protein concentration and plasma protein characteristics, endogenous substances in plasma, total body and extracellular water, fat content, regional blood flow and probably P-glycoprotein, mainly that present in the gut, liver and brain. As far as drug metabolism is concerned, important differences have been found in the pediatric population compared with adults both for phase I enzymes [oxidative (e.g. cytochrome CYP3A7 vs. CYP3A4 and CYP1A2), reductive and hydrolytic enzymes] and phase II enzymes (e.g. N-methyltransferases and glucuronosyltransferases). Finally, key factors undergoing maturational changes accounting for differences in renal excretion in the pediatric population compared with adults are glomerular filtration and tubular secretion. It would be important to generate information on the developmental aspects of renal P-glycoprotein and of other renal transporters as done and still being done with the different isozymes involved in drug metabolism.