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

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Abstract

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.

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Acknowledgments

This work was performed within the framework of Dutch Top Institute Pharma project number D2-104. Dr. de Wildt’s research is supported by Erasmus MC and ZonMW clinical fellowships. The work of C.A.J. Knibbe is supported by the Innovational Research Incentives Scheme (Veni grant, July 2006) of the Dutch Organization for Scientific Research (NWO). Meindert Danhof and Ibrahim Ince have declared no conflicts of interest that are directly relevant to the content of this review.

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Authors and Affiliations

  1. Department of Pediatric Surgery and Intensive Care, Erasmus MC–Sophia Children’s Hospital, Dr. Molewaterplein 60, 3015 GJ, Rotterdam, The Netherlands

    Ibrahim Ince, Catherijne A. J. Knibbe & Saskia N. de Wildt

  2. Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands

    Ibrahim Ince, Catherijne A. J. Knibbe & Meindert Danhof

  3. Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands

    Catherijne A. J. Knibbe

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  1. Ibrahim Ince
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  2. Catherijne A. J. Knibbe
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Correspondence to Saskia N. de Wildt.

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Ince, I., Knibbe, C.A.J., Danhof, M. et al. Developmental Changes in the Expression and Function of Cytochrome P450 3A Isoforms: Evidence from In Vitro and In Vivo Investigations. Clin Pharmacokinet 52, 333–345 (2013). https://doi.org/10.1007/s40262-013-0041-1

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