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Research ArticleArticle

In Vitro Cytochrome P450 Activity Decreases in Children with High Pediatric End-Stage Liver Disease Scores

Lies De Bock, Koen Boussery, Myriam Van Winckel, Peter De Paepe, Xavier Rogiers, Xavier Stephenne, Etienne Sokal and Jan Van Bocxlaer
Drug Metabolism and Disposition February 2013, 41 (2) 390-397; DOI: https://doi.org/10.1124/dmd.112.048504
Lies De Bock
Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University (L.D.B., K.B., J.V.B.), Paediatric Gastroenterology Department, Ghent University Hospital (M.V.W.), Heymans Institute of Pharmacology, Ghent University (P.D.P.), and Surgery Department, Ghent University Hospital, De Pintelaan Gent (X.R.), Ghent, Belgium; and Paediatric Department, Paediatrics Unit, Laboratory of Paediatric Hepatology and Cell Therapy, Catholic University of Louvain and St. Luc Clinics, Brussels (X.S., E.S.), Belgium
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Koen Boussery
Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University (L.D.B., K.B., J.V.B.), Paediatric Gastroenterology Department, Ghent University Hospital (M.V.W.), Heymans Institute of Pharmacology, Ghent University (P.D.P.), and Surgery Department, Ghent University Hospital, De Pintelaan Gent (X.R.), Ghent, Belgium; and Paediatric Department, Paediatrics Unit, Laboratory of Paediatric Hepatology and Cell Therapy, Catholic University of Louvain and St. Luc Clinics, Brussels (X.S., E.S.), Belgium
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Myriam Van Winckel
Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University (L.D.B., K.B., J.V.B.), Paediatric Gastroenterology Department, Ghent University Hospital (M.V.W.), Heymans Institute of Pharmacology, Ghent University (P.D.P.), and Surgery Department, Ghent University Hospital, De Pintelaan Gent (X.R.), Ghent, Belgium; and Paediatric Department, Paediatrics Unit, Laboratory of Paediatric Hepatology and Cell Therapy, Catholic University of Louvain and St. Luc Clinics, Brussels (X.S., E.S.), Belgium
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Peter De Paepe
Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University (L.D.B., K.B., J.V.B.), Paediatric Gastroenterology Department, Ghent University Hospital (M.V.W.), Heymans Institute of Pharmacology, Ghent University (P.D.P.), and Surgery Department, Ghent University Hospital, De Pintelaan Gent (X.R.), Ghent, Belgium; and Paediatric Department, Paediatrics Unit, Laboratory of Paediatric Hepatology and Cell Therapy, Catholic University of Louvain and St. Luc Clinics, Brussels (X.S., E.S.), Belgium
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Xavier Rogiers
Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University (L.D.B., K.B., J.V.B.), Paediatric Gastroenterology Department, Ghent University Hospital (M.V.W.), Heymans Institute of Pharmacology, Ghent University (P.D.P.), and Surgery Department, Ghent University Hospital, De Pintelaan Gent (X.R.), Ghent, Belgium; and Paediatric Department, Paediatrics Unit, Laboratory of Paediatric Hepatology and Cell Therapy, Catholic University of Louvain and St. Luc Clinics, Brussels (X.S., E.S.), Belgium
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Xavier Stephenne
Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University (L.D.B., K.B., J.V.B.), Paediatric Gastroenterology Department, Ghent University Hospital (M.V.W.), Heymans Institute of Pharmacology, Ghent University (P.D.P.), and Surgery Department, Ghent University Hospital, De Pintelaan Gent (X.R.), Ghent, Belgium; and Paediatric Department, Paediatrics Unit, Laboratory of Paediatric Hepatology and Cell Therapy, Catholic University of Louvain and St. Luc Clinics, Brussels (X.S., E.S.), Belgium
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Etienne Sokal
Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University (L.D.B., K.B., J.V.B.), Paediatric Gastroenterology Department, Ghent University Hospital (M.V.W.), Heymans Institute of Pharmacology, Ghent University (P.D.P.), and Surgery Department, Ghent University Hospital, De Pintelaan Gent (X.R.), Ghent, Belgium; and Paediatric Department, Paediatrics Unit, Laboratory of Paediatric Hepatology and Cell Therapy, Catholic University of Louvain and St. Luc Clinics, Brussels (X.S., E.S.), Belgium
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Jan Van Bocxlaer
Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University (L.D.B., K.B., J.V.B.), Paediatric Gastroenterology Department, Ghent University Hospital (M.V.W.), Heymans Institute of Pharmacology, Ghent University (P.D.P.), and Surgery Department, Ghent University Hospital, De Pintelaan Gent (X.R.), Ghent, Belgium; and Paediatric Department, Paediatrics Unit, Laboratory of Paediatric Hepatology and Cell Therapy, Catholic University of Louvain and St. Luc Clinics, Brussels (X.S., E.S.), Belgium
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Abstract

To improve the modeling and simulation of pharmacokinetics in pediatric patients, research into developmental and disease-specific determinants is needed. This article describes the evaluation of the activity of in vitro cytochrome P450 (P450), an important enzyme family in drug metabolism, in children with hepatic dysfunction. The activity of six P450 isoforms (CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4) was evaluated in 31 patients with different pathologies, predominantly biliary atresia (n = 23). Hypervariable activity was observed for all the isoforms. Compared with average adult activity, low activity levels were seen for CYP1A2, 2C19, 2E1, and 3A4. For CYP2E1 and 3A4, a positive correlation between activity and abundance was observed. Age, comedication, and genotype could not be used as predictors for P450 activity in this patient population. In contrast, the pediatric end-stage liver disease score was negatively correlated with the ln(activity). This finding suggests a decrease in P450 activity with deteriorating hepatic function. Moreover, the activity of all isoforms was correlated, demonstrating a concomitant decrease of all isoforms in young patients with liver disease. To our knowledge, this is the first study to evaluate P450 activity in children with hepatic impairment. The presented data may provide support in the further optimization of a disease-specific model in this patient population.

Footnotes

  • This project was financially supported by the Ghent University Special Research Fund [Grant BOF B/09042/02].

  • dx.doi.org/10.1124/dmd.112.048504.

  • Received August 31, 2012.
  • Accepted November 13, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (2)
Drug Metabolism and Disposition
Vol. 41, Issue 2
1 Feb 2013
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Research ArticleArticle

Decreasing P450 Activity with Increasing PELD Score

Lies De Bock, Koen Boussery, Myriam Van Winckel, Peter De Paepe, Xavier Rogiers, Xavier Stephenne, Etienne Sokal and Jan Van Bocxlaer
Drug Metabolism and Disposition February 1, 2013, 41 (2) 390-397; DOI: https://doi.org/10.1124/dmd.112.048504

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Research ArticleArticle

Decreasing P450 Activity with Increasing PELD Score

Lies De Bock, Koen Boussery, Myriam Van Winckel, Peter De Paepe, Xavier Rogiers, Xavier Stephenne, Etienne Sokal and Jan Van Bocxlaer
Drug Metabolism and Disposition February 1, 2013, 41 (2) 390-397; DOI: https://doi.org/10.1124/dmd.112.048504
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