Ontogeny of Phase I Metabolism of Drugs

Abstract

Capturing ontogeny of enzymes involved in phase I metabolism is crucial to improve prediction of dose-concentration and concentration-effect relationships throughout infancy and childhood. Once captured, these patterns can be integrated in semiphysiologically or physiology-based pharmacokinetic models to support predictions in specific pediatric settings or to support pediatric drug development. Although these translational efforts are crucial, isoenzyme-specific ontogeny-based models should also incorporate data on variability of maturational and nonmaturational covariates (eg, disease, treatment modalities, pharmacogenetics). Therefore, this review provides a summary of the ontogeny of phase I drug-metabolizing enzymes, indicating current knowledge gaps and recent progresses. Furthermore, we tried to illustrate that straightforward translation of isoenzyme-specific ontogeny to predictions does not allow full exploration of scenarios of potential variability related to maturational (non-age-related variability, other isoenzymes or transporters) or nonmaturational (disease, pharmacogenetics) covariates, and necessitates integration in a "systems" concept.

Keywords: developmental pharmacology; drug-metabolizing enzymes; ontogeny; phase I metabolism.