title: In vitro cytochrome p450 activity decreases in children with high pediatric end-stage liver disease scores.
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.
authors.affiliation: Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium. Lies.DeBock@UGent.be
authors.forename: Lies
authors.initials: L
authors.lastname: De Bock
authors.forename: Koen
authors.initials: K
authors.lastname: Boussery
authors.forename: Myriam
authors.initials: M
authors.lastname: Van Winckel
authors.forename: Peter
authors.initials: P
authors.lastname: De Paepe
authors.forename: Xavier
authors.initials: X
authors.lastname: Rogiers
authors.forename: Xavier
authors.initials: X
authors.lastname: Stephenne
authors.forename: Etienne
authors.initials: E
authors.lastname: Sokal
authors.forename: Jan
authors.initials: J
authors.lastname: Van Bocxlaer
mesh_terms: D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D058625:End Stage Liver Disease / Q000175:diagnosis / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007527:Isoenzymes; D008099:Liver / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D016031:Liver Transplantation; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010599:Pharmacokinetics; D010641:Phenotype; D012720:Severity of Illness Index
chemical_list: D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System