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

The aim of this review is to discuss our current understanding of the developmental changes of the drug-metabolizing enzyme cytochrome P450 (CYP) 3A and its impact on drug therapy. In the last 10 years, several methods have been used to study the ontogeny of specific CYP3A isoforms in vitro and in vivo. Although most studies confirm previous findings that CYP3A4/5 activity is low at birth and reaches adult values in the first years of life, there are still important gaps in our knowledge of the exact developmental patterns of individual CYP3A isoforms, especially in this age range. Moreover, most in vivo clinical studies have also failed to cover the whole pediatric age range. To date, this information gap still hampers the design of age-specific dosing guidelines of CYP3A substrate drugs, especially in neonates and infants. 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 our understanding of the ontogeny of CYP3A and aid the application of this knowledge in clinical practice.