PT  - JOURNAL ARTICLE
AU  - Lies De Bock
AU  - Koen Boussery
AU  - Myriam Van Winckel
AU  - Peter De Paepe
AU  - Xavier Rogiers
AU  - Xavier Stephenne
AU  - Etienne Sokal
AU  - Jan Van Bocxlaer
TI  - In Vitro Cytochrome P450 Activity Decreases in Children with High Pediatric End-Stage Liver Disease Scores
AID  - 10.1124/dmd.112.048504
DP  - 2013 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 390--397
VI  - 41
IP  - 2
4099  - http://dmd.aspetjournals.org/content/41/2/390.short
4100  - http://dmd.aspetjournals.org/content/41/2/390.full
SO  - Drug Metab Dispos2013 Feb 01; 41
AB  - 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.